D-proline derivatives

ABSTRACT

New compounds have the formula:  
                 
 
     wherein R, R 1 , X and Y have the meanings described herein. Methods are set forth for synthesizing these compounds and using these compounds to treat diseases associated with amyloidosis, such as Alzheimer&#39;s disease, maturity onset diabetes mellitus, familial amyloid polyneuropathy, scrapie, and Kreuzfeld-Jacob disease.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This is a divisional of patent application Ser. No. 09/636,076,filed Aug. 10, 2000, which is a divisional of copending patentapplication Ser. No. 09/505,375, filed Feb. 16, 2000, now U.S. Pat. No.6,262,089, which is a divisional of application Ser. No. 09/179,652,filed Oct. 27, 1998, now U.S. Pat. No. 6,103,910.

BACKGROUND OF THE INVENTION

[0002] 1. Field

[0003] The invention relates to D-prolines and their use in treatingdiseases associated with amyloidosis.

[0004] 2. Description

[0005] The compounds(R)-1-[(R)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acidand (R)-1-[(S)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylicacid are disclosed in WO 97/10225 as having antibacterial activityagainst B. fragilis. These compounds are also disclosed in J.Comput.-Aided Mol. Des., 1(2): 133-42 (1987) in a theoretical study ofangiotensin-converting enzyme inhibitors. However, the use of thesecompounds for treating or preventing central and systemic amyloidosiswas not known before the subject invention.

[0006] The subject invention provides unique D-proline derivatives thatcan be used to treat or prevent central and systemic amyloidosis.Amyloidosis is a disorder of protein metabolism in which normallysoluble autologous proteins are deposited in tissues as abnormalinsoluble fibrils that can cause structural and functional disruption.Disorders associated with amyloidosis include Alzheimer's disease andmaturity onset diabetes mellitus.

SUMMARY OF THE INVENTION

[0007] The invention relates to D-prolines of the formula:

[0008] wherein

[0009] R is SH; benzyl; benzyl substituted by hydroxy or lower alkoxy;phenyl; phenyl substituted by hydroxy or lower alkoxy; or the group

[0010] R¹ is hydrogen or halogen;

[0011] X is —(CH₂)_(n)—; —CH(R²)(CH₂)n—; —CH₂O(CH₂)_(n)—; —CH₂NH—;benzyl; —C(R²)═CH—; —CH₂CH(OH)—; or thiazol-2,5-diyl;

[0012] Y is —S—S—; —(CH₂)_(n)—; —O—; —NH—; —N(R²)—; —CH═CH—; —NHC(O)NH—;—N(R²)C(O)N(R²)—; —N[CH₂C₆H₃(OCH₃)₂]—; —N(CH₂C₆H₅)—;—N(CH₂C₆H₅)C(O)N(CH₂C₆H₅)—; —N(alkoxyalkyl)—; —N(cycloalkyl-methyl)—;2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl;1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl;biphenyl; 1,2-phenylen; 1,3-phenylen; 1,4-phenylen; 1,2-phenylensubstituted by 1 to 4 substituents selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-lower alkyl,nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy,N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl,2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and5-tert-butylsulfanyl-[1,2,4]oxadiazolyl; 1,3-phenylen substituted by 1to 4 substituents selected from the group consisting of halogen, loweralkyl, lower alkoxy, hydroxy, carboxy, -COO-lower alkyl, nitrilo,5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy,N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl,2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and5-tert-butylsulfanyl-[1,2,4]oxadiazolyl; and 1,4-phenylen substituted by1 to 4 substituents selected from the group consisting of halogen, loweralkyl, lower alkoxy, hydroxy, carboxy, —COO-lower alkyl, nitrilo,5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy,N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl,2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;

[0013] X′ is —(CH₂)_(n)—; —(CH₂)_(n)CH(R²)—; —(CH₂)_(n)OCH₂—; —NHCH₂—;benzyl; —CH═C(R²)—; —CH(OH)CH₂; or thiazol-2,5-diyl;

[0014] R² is lower alkyl, lower alkoxy, or benzyl;

[0015]

is a single or a double bond; and

[0016] n is 0-3, and to pharmaceutically acceptable salts and mono- anddiesters thereof, with the exception of(R)-1-[(R)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acidand (R)-1-[(S)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylicacid.

[0017] A method of using these compounds for treating diseasesassociated with amyloidosis by administering to a subject in need ofsuch treatment an effective amount of one of the above-identifiedcompounds or(R)-1-[(R)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acidor (R)-1-[(S)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylicacid is also provided.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The invention will now be described in terms of its preferredembodiments. These embodiments are set forth to aid in understanding theinvention but are not to be construed as limiting.

[0019] The invention provides compounds of the formulas:

[0020] wherein

[0021] R is SH, benzyl or phenyl, optionally substituted by hydroxy orlower alkoxy or the group

[0022] R¹ is hydrogen or halogen;

[0023] X is —(CH₂)_(n)—; —CH(R²)(CH₂)n—; —CH₂O(CH₂)_(n)—; —CH₂NH—;benzyl, —C(R²)═CH—; —CH₂CH(OH)—; or thiazol-2,5-diyl;

[0024] Y is —S—S—; —(CH₂)_(n)—; —O—; —NH—; —N(R²)—; —CH═CH—; —NHC(O)NH—;—N(R²)C(O)N(R²)—; —N[CH₂C₆H₃(OCH₃)₂]—; —N(CH₂C₆H₅)—;—N(CH₂C₆H₅)C(O)N(CH₂C₆H₅)—; —N(alkoxyalkyl)—; —N(cycloalkyl-methyl)—;2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl;1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl;biphenyl; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein thephenylen groups are optionally substituted by 1-4 substituents, selectedfrom halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-loweralkyl, nitrilo, 5-tetrazol, (2-carboxylicacid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl,5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl,5-thioxo-[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;

[0025] X′ is —(CH₂)_(n)—; —(CH₂)_(n)CH(R²)—; —(CH₂)_(n)OCH₂—; —NHCH₂—;benzyl, —CH═C(R²)—; —CH(OH)CH₂; or thiazol-2,5-diyl;

[0026] R² is lower alkyl, lower alkoxy or benzyl and

[0027] n is 0-3, and pharmaceutically acceptable salts or mono- anddiesters thereof, with the exception of (R)-1-[(R)— and(R)-1-[(S)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid.

[0028] The compounds of formulas I-A or I-B may contain 4 or 2asymmetric carbon atoms. Accordingly, the present invention includes allsterioisomeric forms of the compounds of formula I-A or I-B, includingeach of the individual enantiomers and mixtures thereof.

[0029] It has been surprisingly found that the D-prolines of formula I-Aand I-B can be used in the treatment or prevention of all forms ofcentral and systemic amyloidosis, which is a disorder of proteinmetabolism in which normally soluble autologous proteins are depositedin the tissues as abnormal insoluble fibrils, which cause structural andfunctional disruption. The most common disorders associated withamyloidosis are Alzheimer's disease (AD), maturity onset diabetesmellitus, or amyloidosis

[0030] as a significant cause of non-ischaemic heart failure,

[0031] as complication of long term haemodialysis in renal failure,

[0032] as complication of monoclonal gammopathies,

[0033] from chronic inflammatory disorders,

[0034] from chronic infections or

[0035] from certain types of cancer.

[0036] Furthermore, amyloidosis comprises many different diseases suchas forms of hereditary amyloidosis most common familial amyloidpolyneuropathy (FAP), scrapie and Kreuzfeld-Jakob disease.

[0037] The common pathological feature is extracellular deposition of socalled amyloid proteins in B-structured fibers and the same stainingcharacteristics. Serum amyloid P component (SAP) is a normal plasmaprotein and the precursor of amyloid component, a universal constituentof the abnormal tissue deposits in amyloidosis. It is resistant toproteases and therefore plays a key role in the persistance of amyloidin vivo. For therapy pharmaceutically active compounds have to be foundwhich would prevent the interaction of SAP with amyloid fibrils. Thisinteraction has been demonstrated to be a protein fiber interaction,rather than an interaction with more general fiber components such asglycosaminoglycans. SAP consists as a pentamer of 5 identicalnon-covalently associated subunits. Two pentamers can non-covalentlyassociate to a decamer with the two pentameric disk-like ringsinteracting face to face. SAP is a calcium-dependent ligand bindingprotein. It is produced and degraded exclusively in hepatocytes andextremely stabile outside the liver.

[0038] The participation of SAP in the pathogenesis of amyloidosis invivo confirms that inhibition of binding to amyloid fibrils is anattractive therapeutic target in a range of serious human diseases.

[0039] Objects of the present invention are the aforementioned compoundsof formula I-A and I-B and salts and esters thereof per se and astherapeutically active substances, their manufacture and their use fortherapeutic purposes and, respectively, for the production ofcorresponding medicaments as well as medicaments containing a compoundof formula I-A and I-B or a salt thereof and the production of suchmedicaments for said purpose.

[0040] The term “lower alkyl” denotes straight-chain or branched-chainsaturated hydrocarbon residues, preferably with 1-4 C atoms, such asmethyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl, isobutyl andt-butyl.

[0041] “Halogen” denotes chlorine, iodine, fluorine and bromine.Compounds of formula I-A and I-B can form salts with metals, e.g. alkalimetal salts such as sodium or potassium salts or alkaline earth metalsalts such as calcium or magnesium salts, with organic bases, e.g. saltswith amines such as N-ethylpiperidine, procaine or dibenzylamine, orsalts with basic amino acids such as salts with arginine or lysine.These salts can be formed and isolated by methods well known in the art.

[0042] The compounds can also be used in the ester form, such estersbeing aliphatic or aromatic, such as, for example alkyl and phenolicesters. The most preferred esters are alkyl esters derived from C₁₋₄alkanols, especially methyl and ethyl esters. The compounds of formulasI-A and I-B can also be used in form of their prodrugs at either one orboth carbonyl functions. Examples are esters, intramolecular esters,phosphate esters, double esters, glycolamide esters, glycerideconjugates, dihydropyridine derivatives or8-(hydroxymethyl)-1-naphthylmethyldisulfide esters. The prodrugs may addto the value of the present compounds advantages in absorption,pharmacokinetics in distribution and transport to the brain. (WO9514705; H. Bundgaard et al., Drugs of the Future, 16: 443 (1991); A. N.Saab et al., Pharmaceutical Science, 79:802 (1990); D. M. Lambert etal., Current Medical Chemistry, 1:376 (1995).

[0043] Preferred are compounds of formula I-A. Especially preferredcompounds of formula I-A in the scope of the present invention are thosein which X is CH(R²)(CH₂)_(n)— and wherein R² is methyl or methoxy and,n is 0 or 1.

[0044] The following are examples of such compounds:

[0045](R)-1-[(S)-3-[(S)-3-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-methyl-3-oxopropyldisulfanyl]-2-methyl-propionyl]-pyrrolidine-2-carboxylicacid,

[0046](R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl)-2,7-dimethyl-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid,

[0047](R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid and

[0048](R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl)-2,5-dimethyl-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0049] Especially preferred are also compounds, in which X is—(CH₂)_(n)— and n is 0 or 1.

[0050] Such compounds are:

[0051](R)-1-[7-[(R)-2-Carboxy-pyrrolidin-1-yl]-7-oxo-heptanoyl]-pyrrolidine-2-carboxylicacid,

[0052](R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid,

[0053](R)-1-[5-[(R)-2-Carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid,

[0054](R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]acetyl]-pyrrolidine-2-carboxylicacid,

[0055](R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylicacid,

[0056](R)-1-[[Benzyl-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-amino]-acetyl]-pyrrolidine-2-carboxylicacid,

[0057](R)-1-[cis-4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid and

[0058](R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid.

[0059] Preferred are further compounds of formula I-A, wherein X is—CH₂O—.

[0060] Examples of such compounds are the following:

[0061](R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid,

[0062](R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid,

[0063](R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid,

[0064](R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid,

[0065](R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid and

[0066](R)-1-[[5-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid.

[0067] Compounds in which X is —CH₂NH are further preferred.

[0068] An example of such a compound is

[0069](R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid.

[0070] Compounds, in which X is —CH₂CH(OH)— are further preferred.

[0071] Such a compound is, for example,

[0072](2E,4E)-(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylicacid.

[0073] The aforementioned compounds of formula I-A and I-B can bemanufactured in accordance with the invention by

[0074] a) converting a compound of formula

[0075]  into a compound of formula

[0076]  and then into a compound of formula

[0077]  wherein R¹, X and X′ have the significances given above and R²is lower alkyl, or

[0078] b) treating a compound of formula

[0079]  with a compound of formula

[0080]  to a compound of formula I-A by cleaving off the protectinggroup, wherein X, Y and X′ have the significances given above and R⁴ ishydroxy or halogen, or

[0081] c) reacting a compound of formula

[0082]  with an amine of formula NH₂R⁵ and cleaving off the protectinggroup from a compound of formula

[0083]  wherein R¹ and R³ are described as above and R⁵ is hydrogen,lower alkyl, lower alkoxy, benzyl, lower alkoxyalkyl, cycloalkyl-methylor —CH₂C₆H₃(OCH₃)₂, or

[0084] d) reacting a compound of formula

[0085]  with a compound of formula

[0086]  and cleaving off the protecting group of a compound of formula

[0087]  wherein R¹, R³ and X have the significances given above, or

[0088] e) reacting a compound of formula

[0089]  with a compound of formula

[0090]  and cleaving off the protecting group of compounds of formula

[0091]  wherein R¹, R³ and X have the significances given above and R⁷is halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-loweralkyl, nitrilo, 5-tetrazol, (2-carboxylicacid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hyd roxycarbamimidoyl,5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl,5-thioxo-[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl,and m is 0-4, or

[0092] f) cleaving off a protecting group from a compound of formulas

[0093]  wherein R, R¹, X, Y and X′ is as described as above and R³ is aprotecting group, to give a compound of formula I-A or I-B, and, ifdesired,

[0094] converting a compound of formulas I-A and I-B into apharmaceutically usable salt or into a mono- and diester.

[0095] In accordance with process variant (a) a compound of formulaI-A-1 is obtained by converting a compound of formula II, for example1-[(S)-3-acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid, into a compound of formula I-B-1 and then into a compound offormula I-A-1. The reaction is conveniently effected under inertatmosphere at room temperature in the presence of ammonia in a solvent,such as methanol. After stirring for about 2 hours the compound isseparated and subsequently the reaction product can be worked-up to thedesired pure product according to generally known methods.

[0096] The compounds of formula I-A-1 are obtained by stirring the abovecompound in a solution of CuSO₄ in water at room temperature.

[0097] The precise reaction conditions are described in more detail inthe working Examples.

[0098] In accordance with reaction step (b) a protected D-proline istreated with a corresponding dicarboxylic acid or with a correspondingacetyl halide at 0° C. The following dicarboxylic acids are preferred:2,4-dimethylglutaric acid, 2,3-dimethylsuccimic acid,cyclohexane-1,4-dicarboxylic acid, cyclohexane-1,3-dicarboxylic acid,cyclohexane-1,2-dicarboxylic acid, 1,4-phenylenediacetic acid,1,3-phenylenediacetic acid, benzene-1,4-dioic acid, benzene-1,3-dioicacid, pyridine-2,6-dicarboxylic acid, thiophene-2,5-dicarboxylic acid,furan-2,5-dicarboxylic acid, adipic acid, 1,4-phenylenediacetic acid,1,2-phenylenediacetic acid, (4-carboxymethyl-naphthylen-1-yl)aceticacid, (6-carboxymethyl-pyridin-2-yl)acetic acid,(5-carboxymethyl-thiophen-2-yl acetic acid, 2,5-dimethoxy-hexanedioicacid, 2,5-dibenzyl-hex-3-enedioic acid or2,5-diisopropyl-hex-3-enedioxic acid. A detailed procedure is descripedin the Examples in the General Procedure A.

[0099] The reaction step (c) describes the treatment of an amine, forexample propylamine, cyclopropylmethylamine, methoxyethylamine,benzylamine or veratrylamine with a compound of formula IX. Thisreaction is carried out at a temperature between 20 and 80° C. in asolvent, such as acetonitrile.

[0100] In accordance with variant (d) a compound of formula I-B isprepared. To a compound of formula XV in dichloromethane at 0° C. isadded a corresponding bromacetyl derivative, such as bromacetyl bromide,and a compound of formula V. The deprotection is than carried out bymethods known in the art.

[0101] Compounds, in which Y is an optionally substituted 1,2-, 1,3- or1,4-phenylen group, can be prepared in accordance with reaction variant(e). To a compound of formula XV a corresponding dihydroxy-derivative offormula XVII is added. The reaction is carried out in dimethylformamideat room temperature. Preferred are the following dihydroxy-derivatives:hydroquinone, tetrafluorohydroquinone, chorohydroquinone,methoxyhydroquinone, resorcinol, 2,6-dihydroxytoluene,5-methoxyresorcinol, 3,5-dihydroxybenzoate, 3,5-dihydroxybenzonitrile,phloroglucinol, pyrogallol-1-methyl ether, 3-methylcatechol,tetrachlorocatechol, 2,6-dihydroxynaphthalene, 1,5-dihydroxynaphthalene,2,3-dihydroxynaphthalene, 2,2′-dihydroxybiphenyl, 1,4-naphthoquinone or2,7-dihydroxynaphthalene.

[0102] In accordance with process variant (f), a compound of formulasIII or IV is deprotected to a compound of formula I-A or I-B. Suitableprotecting groups and methods for their cleavage will be familiar to anyperson skilled in the art, although of course there can be used onlythose protecting groups which can be cleaved off by methods under theconditions of which other structural elements are not affected. Thetert-butyl group and the benzyl group are preferred O-protecting groups.The process is carried out in conventional manner. For example, acompound of formula III can be dissolved in a suitable solvent ormixture of solvents such as ethanol and ethylacetate, and hydrogenatedin the presence of Pd on carbon at room temperature and atmosphericpressure.

[0103] Pharmaceutically acceptable salts and esters can be manufacturedaccording to methods which are known per se and familiar to any personskilled in the art.

[0104] In schemes 1-9 are described processes for preparation ofcompounds of formulas I-A and I-B, starting from known compounds or fromcompounds, which can be prepared in conventional manner.

[0105] The starting materials of formulas V, VI, VIl, IX, X, XII, XIV,XVII, XX and XXIV are commercial products or can be prepared accordingto methods known per se.

[0106] The preparation of compounds of formulas I-A and I-B aredescribed in more detail in working Examples 1-104.

[0107] wherein R¹, X and X′ have the significances given above, R² islower alkyl and R³ is a protecting group.

[0108] wherein X, Y and X′ have the significances given above and R⁴ ishydroxy or halogen.

[0109] wherein R¹ and R³ are described as above and R⁴ is hydrogen,lower alkyl, lower alkoxy, benzyl, lower alkoxyalkyl, cycloalkyl-methylor —CH₂C₆H₃(OCH₃)₂.

[0110] wherein R¹, R³, X and X′ have the significances given above andR⁶ is hydrogen, lower alkyl, lower alkoxy, or benzyl.

[0111] w wherein R¹, R³ and X have the significances given above.

[0112] wherein R¹, R³ and X have the significances given above and R⁷ ishalogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-lower alkyl,nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy,N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl,2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl and5-tert-butylsulfanyl-[1,2,4]oxadiazolyl, and m is 0-4.

[0113] wherein R¹, R³, R⁵, X and X′ have the significances given above.

[0114] wherein R¹ and R² have the significances given above.

[0115] wherein R³ has the significance given above.

[0116] The preparation of the following examples is described in moredetail:

X Y X′ R R¹ Expl.

—S—S—

— H 1d

— — SH H 1c

—S—S—

— H 2c

— — SH H 2b —(CH₂)₂— —S—S— —(CH₂)₂— — H 3 —(CH₂)₃— —CH₂— —(CH₂)₃— — H 4b—CH(CH₃)CH₂— —(CH₂)₂— —CH₂CH(CH₃)— — H 5 CH(OCH₃)CH₂ —(CH₂)₂——CH₂CH(OCH₃)— — H 6b —(CH₂)₂— —CH₂— —(CH₂)₂— — H 7 —CH₂— —(CH₂)₂— —CH₂—— H 8b (R),(R) —CH₂— —CH₂— —CH₂— — H 9b —CH₂— a bond —CH₂— — H 10b—CH₂O(CH₂)₂— —O— —(CH₂)₂OCH₂— — H 11 —(CH₂)₂—

—(CH₂)₂— — H 12 —CH₂—

—CH₂— — H 13 (R),(R) —CH₂O—

—OCH₃— — H 14b (R),(R) —(CH₂)₂—

—(CH₂)₂— — H 15c —(CH₂)₂— —N[(CH₂)₂CH₃]— —(CH₂)₂— — H 16c —CH₂——NHC(O)NH— —CH₂— — H 17c —(CH₂)₃— —(CH₂)₂— —(CH₂)₃— — H 18 —(CH₂)₂——(CH₂)₂— —(CH₂)₂— — H 19

a bond

— H 20b —CH₂— — —

H 21d —CH₂O—

—OCH₂— — H 22b —CH₂O—

—OCH₂— — H 23b —CH₂O—

—OCH₂— — H 24b —CH₂O—

—OCH₂— — H 25b —CH₂O— — —

H 26b —CH₂O—

—OCH₂— — H 27b —CH₂O— — —

H 28b —CH₂O—

—OCH₂— — H 29b —CH₂O—

—OCH₂— — H 30b —CH₂O—

—OCH₂— — H 31b —CH₂O—

—OCH₂— — H 32 —CH₂O—

—OCH₂— — H 33b —CH₂O—

—OCH₂— — H 34 —CH₂O—

—OCH₂— — H 35b —CH₂O—

—OCH₂— — H 36b —CH₂O—

—OCH₂— — H 37b —CH₂O—

—OCH₂— — H 38b —CH₂O—

—OCH₂— — H 39b —CH₂O—

—OCH₂— — H 40b —CH₂O—

—OCH₂— — H 41b —CH₂O—

—OCH₂— — H 42b —CH₂O—

—OCH₂— — H 43b —CH₂O—

—OCH₂— — H 44b —CH₂O—

—OCH₂— — H 45b —CH₂O—

—OCH₂— — H 46b —CH₂O—

—OCH₂— — H 47b —CH₂O—

—OCH₂— — H 48b —CH₂O—

—OCH₂— — H 49b —CH₂NH—

—NHCH₂— — H 50b —CH₂NH—

—NHCH₂— — H 51b —CH₂— —N[(CH₂)₃CH₃]— —CH₂— — H 52b —CH₂— —N[(CH₂)₂OCH₃]——CH₂— — H 53b —CH₂— —N(CH₂C₆H₅)— —CH₂— — H 54b —CH₂— —N[(CH₂)₃CH₃]——CH₂— — H 55c CO—N[(CH₂)₃CH₃]— —CH₂— — H 55c —CH₂— —N[CH₂C₆H₅]— —CH₂— —H 56c CO—N[CH₂C₆H₅]— —CH₂— — H 56c —CH₂NH— — — benzyl H 57 —CH(CH₃)——CH₂— —CH(CH₃)— — H 58b —CH(CH₃)— a bond —CH(CH₃)— — H 59b a bond

a bond — H 60b a bond

a bond — H 61b a bond

a bond — H 62b a bond

a bond — H 63b —CH₂—

—CH₂— — H 64b —CH₂—

—CH₂— — H 65b a bond

a bond — H 66b a bond

a bond — H 67b a bond

a bond — H 68b a bond

a bond — H 69b a bond

a bond — H 70b —CH₂— —CH₂— —CH₂— — H 71b (S),(S) —CH₂—

—CH₂— — H 72b (S),(S) —CH₂O—

—OCH₂— — H 73b (S),(S) —CH₂—

—CH₂— — H 74d —CH₂—

—CH₂— — H 75d —CH₂—

—CH₂— — H 76e

—(CH₂)₂—

— H 77d

—(CH₂)₂—

— H 78f

—(CH₂)₂—

— H 79 2 diastereomers CH(CH₂C₆H₅) —(CH₂)₂— —CH(CH₂C₆H₅)— — H 80d—CH[(CH₂)₄]— —(CH₂)₂— —CH[(CH₂)₄]— — H 81d —CH[(CH₂)₄]— —(CH₂)₂——CH[(CH₂)₄]— — H 82 2 diastereomers —CH(i-prop.)- —(CH₂)₂— —CH(i-prop.)-— H 83d —CH[(CH₂)₂OCH₃]— —(CH₂)₂— —CH[(CH₂)₂OCH₃]— — H 84d —CH(CH₃)—

—CH(CH₃)— — H 85e 3 diastereomers —C(CH₃)═CH— a bond —CH═C(CH₃)— — H 86b—CH(CH₃)— —(CH₂)₂— —CH(CH₃)— — H 87 —CH₂CH(OH)— a bond —CH(OH)CH₂— — H88c —CH₂— —CH═CH— —CH₂— — H 89d —(CH₂)₂— —N[(CH₂)₂CH₃]— —(CH₂)₂— — H 90c—(CH₂)₂— —N(CH₂cyclopropyl)- —(CH₂)₂— — H 91b —(CH₂)₂——N[CH₂C₆H₃(OCH₃)₂]— —(CH₂)₂— — H 92c —(CH₂)₂— —N[CH₂)₂OCH₃]— —(CH₂)₂— —H 93b —(CH₂)₂— —N(CH₂C₆H₅)— —(CH₂)₂— — H 94b —(CH₂)₂— —NH— —(CH₂)₂— — H95c —(CH₂)₂— —N(CH₂CH₃)— —(CH₂)₂— — H 96 —(CH₂)₂— —N[CH₂C₆H₄CF₃]——(CH₂)₂— — H 97 —CH₂— —(CH₂)₂— —CH₂— — H 98c (R),(S) —CH₂— —(CH₂)₂——CH₂— — H 99c —CH₂— —(CH₂)₂— —CH₂— — F 100e —CH₂O—

—OCH₂— — F 101b —CH₂—

—CH₂— — F 102b —CH₂— —(CH₂)₂— —CH₂— — H, = 103f bond —CH₂O—

—OCH₂— — H, = 104b bond

[0117] As mentioned earlier, the compounds of formulas I-A and I-B havevaluable pharmacological properties. They can be used against all formsof central and systemic amyloidosis, which is a disorder of proteinmetabolism in which normally soluble autologous proteins are depositedin the tissues as abnormal insoluble fibrils, which cause structure andfunctional disruption.

[0118] Compounds of formula I-A and I-B have been tested by thefollowing method:

[0119] Test method

[0120] Binding of SAP (serum amyloid P) to human amyloid Aβ(1-42)fibrils

[0121] Nunc Flouro Polysorp 96 well plates were coated with 0.5 μg/wellof Aβ1-42, which had been aged for 7 days at 37° C. Plates were driedfor 3 days at 37° C., washed with 2×150 μl of TC (10 mM tris, 138 mMNaCl, 6 mM CaCl₂, 0.05% NaN₃ pH 8.0) with 1% bovine serum albumin. Then50 μl TC containing 8% bovine serum albumin, 25 μl compound in TC and 25μl 40 nM [¹²⁵I]serum amyloid protein in TE (10 mM EGTA instead of Ca)were added per well. Incubation was performed over night at roomtemperature and wells were washed twice with 180 μl of TC containing 1%bovine serum albumin. To determine radioactivity 100 μl Microscint 40were added per well and radioactivity was measured in a TopCount(Packard).

[0122] The IC₅₀ (μM) of preferred compounds of formula I-A and I-B arein the range of about 0.2-2.0.

[0123] The compounds of formulas I-A and I-B and their pharmaceuticallyacceptable acid addition salts, their mono- and diesters and cyclicimides thereof can be used as medicaments (e.g. in the form ofpharmaceutical preparations). Pharmaceutical preparations can beadministered orally (e.g. in the form of tablets, coated tablets,dragees, hard and soft gelatine capsules, solutions, emulsions orsuspensions). Administration can, however, also be effected rectally(e.g. in the form of suppositories), parenterally (e.g. in the form ofinjection solutions), or nasally.

[0124] For the manufacture of pharmaceutical preparations, the compoundsof formulas I-A and I-B and the pharmaceutically acceptable acidaddition salts and esters thereof can be processed with pharmaceuticallyinert, inorganic or organic carriers. Lactose, corn starch orderivatives thereof, talc, stearic acid or its salts and the like can beused, for example, as such carriers for tablets, coated tablets, drageesand hard gelatine capsules. Suitable carriers for soft gelatine capsulesare, for example, vegetable oil, waxes, fats, semi-solid and liquidpolyols and the like. Depending on the nature of the active substance nocarriers are, however, usually required in the case of soft gelatinecapsules. Suitable carriers for the manufacture of solutions and syrupsare, for example, water, polyols, glycerol, vegetable oils and the like.Suitable carriers for suppositories are, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0125] The pharmaceutical preparations can, moreover, containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, coating agents or antioxidants. They can also containother therapeutically valuable substances.

[0126] Medicaments containing a compound of formulas I-A or I-B or apharmaceutically acceptable acid addition salt or mono- and diestersthereof and a therapeutically inert barrier are also an object of thepresent invention, as is a process for their manufacture which comprisesbringing one or more compounds of formulas I-A and I-B and/orpharmaceutically acceptable acid addition salts and mono- and diestersthereof into a galenical administration form together with one or moretherapeutically inert carriers.

[0127] In accordance with the invention, compounds of formulas I-A andI-B as well as their pharmaceutically acceptable acid addition salts andmono- and diesters thereof can be used used in the treatment orprevention of central and systemic amyloidosis.

[0128] The most common disorders associated with amyloidosis areAlzheimer's disease (AD), maturity onset diabetes mellitus, oramyloidosis

[0129] as a significant cause of non-ischaemic heart failure,

[0130] as complication of long term haemodialysis in renal failure,

[0131] as complication of monoclonal gammopathies,

[0132] from chronic inflammatory disorders,

[0133] from chronic infections and

[0134] from certain types of cancer.

[0135] Furthermore, amyloidosis comprises many different diseases suchas forms of hereditary amyloidosis, most commonly familial amyloidpolyneuropathy (FAP), scrapie and Kreuzfeld-Jakob disease.

[0136] Furthermore, the present compounds can be used for themanufacture of corresponding medicaments. The dosage can vary withinwide limits and will, of course, be fitted to the individualrequirements in each particular case. In the case of oral administrationthe dosage lies in a range of about 0.1 mg per dosage to about 5,000 mgper day of a compound of formulas I-A or I-B or the corresponding amountof a pharmaceutically acceptable acid addition salt or mono- anddiesters thereof. The upper limit can, of course, be exceeded whenindicated to be appropriate.

[0137] The following Examples illustrate the present invention in moredetail. However, they are not intended to limit its scope in any manner.All temperatures are given in degrees Celsius.

EXAMPLE 1(R)-1-[(S)-3-[(S)-3-[(R)-2-carboxy-pyrrolidin-1-yl]-2-methyl-3-oxopropyldisulfanyl]-2-methyl-propionyl]-pyrrolidine-2-carboxylicacid

[0138] a)1-[(S)-3-(Acetylsulfanyl)-20-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid tert-butylester and1-[(R)-3-(Acetylsulfanyl)-20-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid tert-butylester

[0139] 18.6 ml Triethylamine were given at 0-5° C. to a solution of 23.2g (135 mmol) D-proline-tert-butylester in 230 ml dry dichloromethane. Asolution of 24.5 g (135 mmol)S-(3-chloro-2-methyl-3-oxopropyl)ethanethioic acid ester in 116 mldichloromethane were added at this temperature over a period of 1 hourand stirring was continued at room temperature for 2 hours. Theprecipitate was removed by filtration. The solution was washed withwater and dried with sodium sulfate. Evaporation of the solvent atreduced pressure gave 41.4 g colorless oil which was chromatographed on4 kg silicagel with ether/cylohexane 2/1 yielding 19.6 g (46%)1-[(R)-3-(acetylsulfanyl)-20-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid tert-butylester and 18.2 g (43%)1-[(S)-3-(Acetylsulfanyl)-20-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid tert-butylester and 1.6 g mixture of epimers.

[0140] MS m/e(%)=315 (M⁺, 3), 259(10), 242(10), 214(100), 172(10),145(32), 70(22); [a]_(D)=−0.7° (1% EtOH).

[0141] MS m/e(%)=315 (M⁺, 4), 259(7), 242(9), 214(100), 172(9), 145(33),70(33); [a]_(D)=+156.7° (1% EtOH).

[0142] b)1-[(S)3-Acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid

[0143] 15.45 g (48.9 mmol)1-[(S)-3-(Acetylsulfanyl)-20-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid tert-butylester were stirred with 99 ml trifluoric acid and 55 mlanisole under argon for three hours. The mixture was evaporated undervacuum. The residue was dissolved in about 100 ml ice cold ethylacetateand washed with about 200 ml of an icecold aqueous solution ofsodiumbicarbonate. Concentrated hydrochloric acid was added untericecooling until ph 1-2. The aqueous phase was extracted four times withicecold ethylacetate, dried with sodium sulfate and evaporated. Theyield was 11.6 g (91%)1-[(S)3-acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid that was used without further purification.

[0144] [a]_(D)=−11.8° (0.6% EtOH).

[0145] c)1-[(S)3-Mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acid

[0146] 11.59 g (44.69 mmol)1-[(S)3-acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid were dissolved at room temperature under argon in 70 ml argonwashed methanol. After addition of 70 ml 10N ammonia in methanolstirring was continued for two hours at room temperature. Then thesolvent was distilled off under vacuum. The residue was taken up with 5%aqueous KHSO₄ solution and extracted six times with withdichloromethane. The organic layers were washed twice with 5% aqueousKHSO₄ solution, three times with 1 N hydrochloric acid and dried oversodiumsulfate. Evaporation of the solvent and crystallization fromethylacetate/hexane yielded 6.25 (64%)1-[(S)3-mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acidwith melting point 99-101° C.

[0147] a]_(D)=+40.7° (1% EtOH).

[0148] d)1-[(S)3-Mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acid

[0149] A solution of 749 mg (3.0 mmol) CuSO₄×5 H₂O in 90 ml water wasadded at room temperature to a solution of 651.85 mg (3.0 mmol)1-[(S)3-mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acidin 90 ml dichloromethane. The mixture was vigorously stirred for 10minutes and filtered. The aqueous phase was washed 5 times withdichloromethane, the organic phases were washed with brine and driedwith magnesiumsulfate and the solvent was removed under vacuum.Crystallization from dichloromethane/hexane gave 275.3 mg (43%)(R)-1-[(S)-3-[(S)-3-[(R)-2-carboxy-pyrrolidin-1-yl]-2-methyl-3-oxopropyldisulfanyl]-2-methyl-propionyl]-pyrrolidine-2-carboxylicacid with melting point 142-144° C.

[0150] [a]_(D)=+42.8° (1% CHCl₃).

EXAMPLE 2(R)-1-[(R)-3-[(R)-3-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-methyl-3-oxo-propyldisulfanyl)-2-methyl-propionyl]-pyrrolidine-2-carboxylicacid

[0151] a)1-[(R)3-Acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid

[0152] 18.9 g (60.0 mmol)1-(3-acetylsulfanyl-2-methyl-propionyl)-pyrrolidine-2-carboxylic acidtert-butyl ester were stirred with 120 ml trifluoric acid and 75 mlanisole under argon for three hours. The mixture was evaporated undervacuum. The residue was dissolved in icecold ethylacetate and washedwith an icecold aqueous solution of sodiumbicarbonate. Concentratedhydrochloric acid was added unter icecooling until ph 2-3. The aqueousphase was extracted three times with icecold ethylacetate, dried withsodium sulfate and evaporated. The yield was 15.3 g (98%)1-[(R)3-acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid that was used without further purification.

[0153] [a]_(D)=+127.8° (1% EtOH).

[0154] b)1-[(R)3-Mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acid

[0155] 2.98 g (11.5 mmol)1-[(R)3-Acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicwere dissolved at room temperature under argon in 15 ml argon washedmethanol. After addition of 15 ml 10N ammonia in methanol stirring wascontinued for two hours at room temperature. Then the solvent wasdistilled off under vacuum at room temperature. The residue was taken upwith 5% aqueous KHSO₄ solution and extracted six times with withdichloromethane and three times with ethylacetate. The organic layerswere washed twice with 5% aqueous KHSO₄ solution, three times with 1 Nhydrochloric acid and dried over sodiumsulfate. Evaporation of thesolvent and crystallization from ethylacetate/hexane yielded 1.59 g(64%) 1-[(R)3-mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylicacid with melting point 98-100°C.

[0156] [a]_(D)=+128.8° (1% EtOH).

(R)-1-[(R)-3-[(R)-3-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-methyl-3-oxopropyldisulfanyl)-2-methyl-propionyl]-pyrrolidine-2-carboxylicacid

[0157] Analogous to example 1d):

[0158] MS m/s (%): 432(M⁺, 2) 217(100), 184(76), 172(67), 142(13),70(79), 41(21).

EXAMPLE 3(R)-1-[3-[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyldisulfanyl]-propionyl]-pyrrolidine-2-carboxylicacid

[0159] 0.9 g (4 mmol)1-(3-mercapto-propionyl)-(R)-pyrrolidine-2-carboxylic acid (rawmaterial) were dissolved in dichloromethane and extracted with 50 ml ofan saturated aqueous solution of CuSO₄. The aqueous phase was extractedtwice with dichloromethane, the combined organic phases filtered, driedwith magnesiumsulfate and evaporated. Chromatography withdichloromethane/acetone/formic acid 80/20/1 gave 70 mg(R)-1-[3-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyldisulfanyl]-propionyl]-pyrrolidine-2-carboxylicacid as a colorless oil.

[0160] ISN-MS: 403 (M−H)⁻.

EXAMPLE 4(R)-1-[9-[(R)-2-Carboxy-pyrrolidin-1-yl]-9-oxo-nonanoyl]pyrrolidine-2-carboxylicacid

[0161] a)(R)-1-[9-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-9-oxo-nonanoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0162] 0.97 g (4 mmol) D-proline-benzylester hydrochloride in 25 mldichloromethane were stirred with 450 mg (2 mmol) azelaoyl chloride and1.12 ml (8 mmol) triethylamine for 20 hours under argon at roomtemperature. Extraction with 2N hydrochloric acid and brine, drying withsodiumsulfate and evaporation gave 1.2 g oil which was chromatographedover silicagel with acetoacetate to yield 0.9 g (80%)(R)-1-[9-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-9-oxo-nonanoyl]-pyrrolidine-2-carboxylicacid benzyl ester as colorless oil.

[0163]¹H-NMR (CDCl₃, ppm): 1.1-2.4 (m, 22H), 3.4-3.7 (m, 4H), 4.4-4.6(m, 2H), 5.1-5.3 (2×AB, 4H), 7.34 (m, 10H).

[0164] b)(R)-1-[9-[(R)-2-Carboxy-pyrrolidin-1-yl]-9-oxo-nonanoyl]pyrrolidine-2-carboxylicacid,

[0165] 100 mg (0.18 mmol)(R)-1-[9-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-9-oxo-nonanoyl]-pyrrolidine-2-carboxylicacid benzyl ester in 20 ml ethanol were hydrogenated in the presence of20 mg 5% Pd on carbon for two hours at room temperature. Filtration andevaporation gave 60 mg(R)-1-[9-[(R)-2-carboxy-pyrrolidin-1-yl]-9-oxo-nonanoyl]pyrrolidine-2-carboxylicacid, as a colorless oil.

[0166] ISP-MS: 383 (MH⁺).

EXAMPLE 5(R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl)-2,7-dimethyl-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid

[0167] 1.2 g (5, 0 mmol) 2,7-dimethyl-octanedioylic chloride weredissolved in 100 ml dimethylformamid, 1.15 g (10 mmol) D-proline and 1.4ml (10 mmol) triethylamine were added and the mixture warmed to 50° C.for five minutes. Stirring was continued at room temperature over night.The solvent was distilled off and the residue taken up in 30 ml 2Nhydrochloric acid. Extraction with ethylacetate, drying withsodiumsulfate, evaporation and chromatography over silicagel withchloroform/acetone/formic acid 80/15/5 gave 0.11 g(R)-1-[8-[(R)-2-carboxy-pyrrolidin-1-yl)-2,7-dimethyl-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid as colorless oil.

[0168] ISP-MS: 397 (MH)⁺.

EXAMPLE 6(R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid

[0169] a)(R)-1-[8-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0170] To 0.25 g (1.1 mmol) 2,7-dimethoxy-octanedioic acid in a mixtureof 25 ml tetrahydrofuran and 20 ml dichloromethane was added a solutionof 0.35 g (2.1 mmol) carbonyldiimidazole in 15 ml tetrahydrofuran. Afterstirring at room temperature for two hours 0.52 g (2.16 mmol)D-proline-benzylester hydrochloride in 10 ml dichloromethane and 0.54 gtriethylamine were added and stirring was continued for 18 hours.

[0171] After filtration the solvent was distilled off and the residuedissolved in ethylacetate and extracted with 2N hydrochloric acid andwater. Drying with sodiumsulfate, evaporation of the solvent andchromatography over silicagel with ethylaceteate yielded 0.21 g(R)-1-[8-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid benzyl ester as a colorless oil.

[0172] S-ISP: 609 (M+H)⁺.

[0173] b) (R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylic acid

[0174] 182 mg (0.3 mmol)(R)-1-[8-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid benzyl ester in 10 ml methanol were hydrogenated in the presence of30 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded109 mg (84%)(R)-1-[8-[(R)-2-carboxy-pyrrolidin-1-yl]-2,7-dimethoxy-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid as colorless oil.

[0175] MS: 427 (M−H)⁻.

EXAMPLE 7(R)-1-[7-[(R)-2-Carboxy-pyrrolidin-1-yl]-7-oxo-heptanoyl]-pyrrolidine-2-carboxylicacid

[0176] A mixture of 0.99 g (5 mmol) pimeloyl chloride, 1.15 g (10 mmol)D-proline and 1.4 ml (10 mmol) triethylamine in 100 ml dimethylformamidewas warmed until a clear solution was obtained and then stirredovernight at ambient temperature. The solvent was distilled off undervacuum. The residue was taken up with 2N hydrochloric acid and extractedwith dichloromethane. Evaporation of the solvent and chromatography oversilicagel with chloroform/aceton/formic acid 80/15/5 yielded 0.27 g(R)-1-[7-[(R)-2-carboxy-pyrrolidin-1-yl]-7-oxo-heptanoyl]-pyrrolidine-2-carboxylicacid as an oil.

[0177] MS: 353 (M−H)⁻.

EXAMPLE 8(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0178] a)(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0179] 0.97 g (10 mmol) D-proline-benzylester hydrochloride in 70 mldichloromethane were stirred with 0.92 g (5 mmol) adipoyl chloride and2.8 ml (20 mmol) triethylamine over the weekend under argon at roomtemperature. Extraction with 2N hydrochloric acid and water, drying withsodiumsulfate, evaporation and chromatography over silicagel withacetoacetate to yielded 0.42 g (16%)(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester as colorless oil.

[0180] MS-ISP: 521 (M+H)⁺.

[0181] b)(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0182] 410 mg (0.79 mmol)(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester in 100 ml methanol were hydrogenated in the presenceof 50 mg 5% Pd on carbon. Filtration and evaporation of the solventyielded 160 mg (59%)(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid as colorless oil.

[0183] MS: 339 (M−H)⁻.

EXAMPLE 9(R)-1-[5-[(R)-2-Carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid

[0184] a)(R)-1-[5-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0185] 0.97 g (10 mmol) D-proline-benzylester hydrochloride in 70 mldichloromethane were stirred with 0.85 g (5 mmol) glutaryl dichlorideand 2.8 ml (20 mmol) triethylamine over night under argon at roomtemperature. Extraction with 2N hydrochloric acid and brine, drying withsodiumsulfate, evaporation and chromatography over silicagel withacetoacetate to yielded 0.44 g (17%)(R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid benzyl ester as colorless oil.

[0186] MS-ISP: 507 (M+H)⁺.

[0187] b)(R)-1-[5-[(R)-2-Carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid

[0188] 440 mg (0.87 mmol)(R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid benzyl ester in 100 ml ethanol were hydrogenated in the presence of40 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded130 mg (46%)(R)-1-[5-[(R)-2-carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid as colorless oil.

[0189] MS-ISP: 327 (M+H)⁺.

EXAMPLE 10(R)-1-[4-[(R)-2-Carboxy-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid

[0190] a)(R)-1-[4-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid benzyl ester

[0191] To a solution of 300 mg (1.2 mmol) D-Proline benzyl esterhydrochloride and 0.35 ml (2.5 mmol) triethylamine in 9 mldichloromethane at 0° C. was added dropwise 68 ml (0.6 mmol) succinylchloride and stirring continued for 24 h at room temperature. Thereaction mixture was then washed sequentially with saturated ammoniumchloride solution, saturated sodium bicarbonate solution and finallywith water, and the aqueous phases back-extracted with dichloromethane.The combined organic extracts were dried over sodium sulphate andconcentrated in vacuo to afford 286 mg (94%) of the title compound as apale yellow oil.

[0192] MS m/e (%): 510 (M+NH4⁺, 20), 493 (M+H⁺, 100), 288 (80).

[0193] b)(R)-1-[4-[(R)-2-Carboxy-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid

[0194] A solution of 256 mg (0.5 mmol)(R)-1-[4-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid benzyl ester in 5 ml ethanol was stirred with 13 mg 10% Palladiumon carbon under 1 atm of hydrogen for 16 h at room temperature. Afterfiltration to remove the catalyst, concentration in vacuo afforded 170mg (100%) of the title compound(R)-1-[4-[(R)-2-carboxy-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid as a colorless viscous oil.

[0195] MS m/e (%): 313 (M+H)⁺, 100).

EXAMPLE 11(R)-1-[[2-[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]ethoxy]-ethoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0196] A mixture of 1.04 g (4 mmol) 2,2′-[oxybis(2,1-ethanediyloxy)]bisacetyl chloride, 0.92 g (8 mmol) D-proline and 1.2 ml triethylamine in200 ml dimethylformamide was stirred for three days at ambienttemperature. The solvent was distilled off under vacuum. The residue waschromatographed over silicagel with methanol to yield 0.42 g(R)-1-[[2-[2-[2-[(R)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]ethoxy]-ethoxy]-acetyl]-pyrrolidine-2-carboxylicacid as a beige hygroscopic solid.

[0197] MS-ISP: 417 (M+H)⁺.

EXAMPLE 12(R)-1-[3-[4-[3-[(R)-2-Carboxy-pyrrolidin-1-yl)-3-oxo-propyl]-phenyl]-propionyl]-pyrrolidine-2-carboxylicacid

[0198] A mixture of 1.30 g (5 mmol) 1,4-benzene dipropanoyl dichloride,1.15 g (10 mmol) D-proline and 1.5 ml triethylamine in 100 mldimethylformamide was stirred for 24 hours at ambient temperature. Thesuspension was filtered and the solvent was distilled off under vacuum.The residue was taken up in acetoacetate, washed with 2N hydrochloricacid, dried over sodiumsulfate and chromatographed over silicagel withdichloromethane/acetone/formic acid 80/5/15 to yield 0.48 g(R)-1-[3-[4-[3-[(R)-2-carboxy-pyrrolidin-1-yl)-3-oxo-propyl]-phenyl]-propionyl]-pyrrolidine-2-carboxylicacid as colorless foam.

[0199] MS-ISP: 417 (M+H)⁺.

EXAMPLE 13(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]acetyl]-pyrrolidine-2-carboxylicacid

[0200] A mixture of 1.15 g (5 mmol) 1,4-benzene diacetyl dichloride,1.15 g (10 mmol) D-proline and 1.5 ml triethylamine in 100 mldimethylformamide was stirred for 20 hours at ambient temperature. Thesolvent was distilled off under vacuum. The residue was taken up in 30ml 2N hydrochloric acid, treated with ultrasound, filtered and dried toyield 1.19 g of a brown solid. This was stirred and refluxed for 30minutes in 300 ml methanol. Filtration, evaporation andrecrystallization from methanol/acetoacetate gave 0.18 g(R)-1-[[4-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]acetyl]-pyrrolidine-2-carboxylicacid as yellow crystals with melting point 210-214° C.

[0201] MS-ISP: 389 (M+H)⁺.

EXAMPLE 14(R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0202] a)(R)-1-[[2-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]acetyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0203] To 0.566 g (2.5 mmol) 1,2-phenylenedioxyacetic acid in 60 mltetrahydrofuran was added a solution of 0.81 g (5 mmol)carbonyldiimidazole in 25 ml tetrahydrofuran.

[0204] After stirring at room temperature for two hours 1.21 g (5 mmol))D-proline-benzylester hydrochloride in 30 ml dichloromethane and 1.4 mltriethylamine were added and stirring was continued over the weekend.

[0205] The mixture was extracted with 2N hydrochloric acid and brine.Drying with sodiumsulfate, evaporation of the solvent and chromatographyover silicagel with ethylaceteate yielded 0.25 g(R)-1-[[2-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]acetyl]-pyrrolidine-2-carboxylicacid benzyl ester as colorless oil.

[0206] MS m/e (%): 600 (1,M⁺), 509 (1), 368 (25), 246 (17), 217 (19),204 (14), 91 (100).

[0207] b)(R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0208] 230 mg (0.38 mmol)(R)-1-[[2-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]acetyl)-pyrrolidine-2-carboxylicacid benzyl ester in 100 ml ethanol were hydrogenated in the presence of30 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded0.2 g(R)-1-[[2-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid as colorless glass (that still contained small amounts of ethanol)

[0209] MS-ISP: 421 (M+H)⁺.

EXAMPLE 15(R)-1-[3-[6-[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]propionyl]-pyrrolidine-2-carboxylicacid

[0210] a) 3-[6-(2-Carboxy-ethyl)-pyridin-2-yl]-propionic acid

[0211] A mixture of 25.6 g (0.2 mol) naphthalin and 1.39 g (0.2 mol)lithium in 150 ml tetrahydrofurane was stirred for three hours at roomtemperature. After cooling to −15° C. a solution of 5.72 ml (0.1 mol)acetic acid in 10 ml tetrahydrofurane was added and stirring wascontinued for three hours at room temperature. Then 13.3 g (0.5 mol)2,6-bis-(bromomethyl)pyridine in 65 ml tetrahydrofurane was added andstirring was continued over night at room temperature. 200 ml ether wereadded and the mixture was extracted with water. The water layers werefiltered through 200 ml BioRad AG1-X8 ion exchanger. The ion exchangerwas washed with water until neutral and then eluated with aceticacid/water. Product containing fractions were evaporated, dissolved inwater and lyophylized to yield 3.9 g (35%)3-[6-(2-carboxy-ethyl)-pyridin-2-yl]-propionic acid as a light yellowpowder.

[0212] MS m/e (%): 223 (M⁺, 15), 178(100), 160(81), 132(68), 104(16),77(13).

[0213] b)(R)-1-[3-[6-[3-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0214] To 0.45 g (2.0 mmol)3-[6-(2-carboxy-ethyl)-pyridin-2-yl]-propionic acid in a mixture of 25ml tetrahydrofuran and 25 ml dichloromethane was added a solution of0.65 g (4.0 mmol) carbonyldiimidazole in 20 ml tetrahydrofuran. Afterstirring at room temperature for two hours 0.97 g (4.0 mmol)D-proline-benzylester hydrochloride in 50 ml dichloromethane and 1.12 gtriethylamine were added and stirring was continued for 18 hours.

[0215] Then ethylacetate was added to the mixture followed by extractionwith water. Drying with sodiumsulfate, evaporation of the solvent andchromatography over silicagel with ethylaceteate/hexane 2/8, thenethylacetate, then ethylacetate/methanol 95/5 followed by a secondchromatography of the product containing fractions on silicagel withaceton/hexane 6/4 yielded 0.18 g (15%)(R)-1-[3-[6-[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester as a colorless oil.

[0216] MS-ISP: 598 (M+H)⁺.

[0217] c)(R)-1-[3-[6-[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]propionyl]-pyrrolidine-2-carboxylicacid

[0218] 0.17 g (0.29 mmol)(R)-1-[3-[6-[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester in 100 ml ethanol were hydrogenated in the presence of35 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded0.11 g (92%)(R)-1-[3-[6-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]propionyl]-pyrrolidine-2-carboxylicacid as colorless oil.

[0219] MS-ISP: 418 (M+H)⁺.

EXAMPLE 16(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid

[0220] a) (R)-1-Acryloyl-pyrrolidine-2-carboxylic acid benzyl ester

[0221] To a solution of 390 mg (1.6 mmol) D-Proline benzyl esterhydrochloride and 0.47 ml (3.4 mmol) triethylamine in 20 mldichloromethane at 0° C. was added dropwise 0.2 ml (2.4 mmol) acryloylchloride and stirring continued for 24 h at room temperature. Thereaction mixture was then washed sequentially with water, 1 Mhydrochloric acid and once more with water, and the aqueous phasesback-extracted with dichloromethane. The combined organic extracts weredried over sodium sulphate and concentrated in vacuo to afford 420 mg(100%) of the title compound (R)-1-acryloyl-pyrrolidine-2-carboxylicacid benzyl ester as a colorless oil.

[0222] MS m/e (%): 259 (M⁺, 25), 124 (100), 91 (25), 70 (21).

[0223] b)(R)-1-[3-[[3-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0224] A solution of 400 mg (1.5 mmol)(R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester and 63 ml(0.75 mmol) propylamine in 5 ml acetonitrile was stirred for 16 h atroom temperature, then for 6 h at 45° C., and finally for 16 h at 80° C.Concentration in vacuo and flash chromatography (20% H₂O in acetone)afforded 84 mg (19%) of the title compound(R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester as a pale yellow oil.

[0225] MS m/e (%): 578 (M+H⁺, 100).

[0226] c)(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid

[0227] A solution of 84 mg (0.15 mmol)(R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester in 3 ml ethanol was stirred with 10 mg 10% palladiumon carbon under 1 atm of hydrogen for 16 h at room temperature. Afterfiltration to remove the catalyst, concentration in vacuo afforded 58 mg(100%) of the title compound(R)-1-[3-[[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid as a white solid.

[0228] MS m/e (%): 398 (M+H⁺, 100).

EXAMPLE 17(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylicacid

[0229] a) (R)-1-tert-Butoxycarbonylaminoacetyl-pyrrolidine-2-carboxylicacid benzyl ester

[0230] 1.21 g (5 mmol) D-proline-benzylester hydrochloride weredissolved in 100 ml dichloromethane and stirred with 0.7 mltriethylamine. The mixture was extracted with water, dried withsodiumsulfate and evaporated. The residue was dissolved in a mixture of100 ml tetrahydrofuran and 50 ml chloroform. 1.03 g (5 mmol)N,N′-dicyclohexylcarbodiimide and 0.88 g (5 mmol) BOC-glycin were addedand stirring was continued for 18 hours at room temperature. Five dropsacetic acid were added and after 10 minutes at room temperature themixture was filtered and the solvents were distilled off. The residuewas taken up in acetoacetate, washed with aqueous citric acid, withaqueous sodiumbicarbonate and water, dried with sodiumsulfate and thesolvent was distilled off. Chromatography over silicagel withdichloromethane/methanol 99/1 yielded 1.43 g (79%)(R)-1-tert-butoxycarbonyl-aminoacetyl-pyrrolidine-2-carboxylic acidbenzyl ester as colorless oil.

[0231] MS m/e (%): 363 (M+H⁺, 1), 306 (29), 289 (10), 114 (44), 91 (76),70 (100), 57 (64).

[0232] b)(R)-1-[[3-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylicacid benzyl ester

[0233] 8.6 ml trifluoric acid were added dropwise at 0° C. to a solutionof 1.57 g (4.34 mmol)(R)-1-tert-butoxycarbonylaminoacetyl-pyrrolidine-2-carboxylic acidbenzyl ester in 8.6 ml dichloromethane and stirring was continued forhalf an hour at room temperature. The solution was washed with aqueoussodiumbicarbonate, dried with sodiumsulfate and evaporated. The residuewas dissolved in 200 ml dichloromethane and stirred with 0.21 g (0.7mmol) triphosgene and 1.8 ml (13 mmol) triethylamine for four hours atroom temperature. The mixture was extracted with 1N hydrochloric acid,dried with sodiumsulfate and evaporated. The remaining 1.15 g residuewere chromatographed over silicagel with dichloromethane/methanol 96/4and the fractions containing product were chromatographed again oversilicagel with dichloromethane/acetone/formic acid 80/15/5 to yield 0.23g (33%)(R)-1-[[3-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylicacid benzyl ester as an oil.

[0234] MS-ISP: 551 (M+H)⁺.

(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylicacid

[0235] 0.14 g (0.36 mmol)(R)-1-[[3-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylicacid benzyl ester in 60 ml ethanol were hydrogenated in the presence of40 mg 5% Pd on carbon. Filtration, evaporation of the solvent andcrystallization from methanol/ethylacetate yielded 0.07 g ( 52%) aswhite crystals with melting point 157-160° C.

EXAMPLE 18(R)-1-[10-[(R)-2-Carboxy-pyrrolidin-1-yl]-10-oxo-decanoyl]-pyrrolidine-2-carboxylicacid Ca salt (1:1)

[0236] A mixture of 1.20 g (5 mmol) sebacoyl chloride, 1.15 g (10 mmol)D-proline and 1.4 ml (10 mmol) triethylamine in 100 ml dimethylformamidewas stirred over the weekend at ambient temperature. The solvent wasdistilled off under vacuum. The residue was taken up with 40 ml aqueouscitric caid acid and extracted with ethylacetate. Evaporation of thesolvent and chromatography over silicagel with chloroform/aceton/formicacid 80/5/15 yielded 1.21 g(R)-1-[10-[(R)-2-carboxy-pyrrolidin-1-yl]-10-oxo-decanoyl]-pyrrolidine-2-carboxylicacid as an oil.

[0237] MS-ISP: 397 (M+H)⁺.

[0238] 0.89 g (2.24 mmol) of this oil were dissolved in 50 ml ethanoland stirred with 0.175 g (2.24 mmol) calciumhydroxide for 48 hours. Thesuspesion was filtered. The solid residue was taken up in 15 ml water,warmed to 80° C., filtrated when hot and evaporated. The residue wassuspended in ether, filtered and washed with ether to yield 0.5 g(R)-1-[10-[(R)-2-carboxy-pyrrolidin-1-yl]-10-oxo-decanoyl]-pyrrolidine-2-carboxylicacid Ca salt (1:1) as a white solid.

[0239] C (theory) 55.28 H (theory) 6.96 N (theory) 6.45

[0240] C (found) 55.29 H (found) 7.11 N (found) 6.08

EXAMPLE 19(R)-1-[8-[(R)-2-Carboxy-pyrrolidin-1-yl)-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid Ca salt (1:1)

[0241] A mixture of 1.10 g (5 mmol) suberoyl chloride, 1.15 g (10 mmol)D-proline and 1.5 ml (10 mmol) triethylamine in 100 ml dimethylformamidewas stirred over 20 hours at ambient temperature. The solvent wasdistilled off under vacuum. The residue was taken up with 40 ml aqueouscitric caid acid and extracted with ethylacetate. Evaporation of thesolvent and chromatography over silicagel with chloroform/aceton/formicacid 80/5/15 yielded 0.8 g(R)-1-[8-[(R)-2-carboxy-pyrrolidin-1-yl)-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid as an oil.

[0242] MS-ISN: 367 (M−H)⁻.0.79 g (2.15 mmol) of this oil were dissolvedin 40 ml ethanol and stirred with 0.167 g (2.15 mmol) calciumhydroxidefor 20 hours. The suspension was filtered and the solid residue wasalmost dissolved in 25 ml water. The solution was filtrated andevaporated to yield 0.5 g(R)-1-[8-[(R)-2-carboxy-pyrrolidin-1-yl)-8-oxo-octanoyl]-pyrrolidine-2-carboxylicacid Ca salt (1:1) as a white solid.

EXAMPLE 20(R)-1-[4′-[(R)-2-Carboxy-pyrrolidin-1-yl-carbonyl]-[2,2]-bithiazolyl-4-yl]pyrrolidine-2-carboxylicacid

[0243] a)(R)-1-[4′-[(R)-2-Carboxypyrrolidin-1-yl-carbonyl]-[2,2]-bithiazolyl-4-yl]pyrrolidine-2-carboxyolicacid benzyl ester

[0244] Thionylchloride (2 ml ) was added to a solution of 0.26 g(1 mmol)[2,2′]bithiazolyl-4,4′-dicarboxylic acid in 20 ml tetramethylurea andthe mixture was stirred for three days at room temperature. Excessthionylchloride and the solvent were distilled off under vacuum. Theresidue was three times taken up in dimethylformamide and evaporated andthen dissolved in 50 ml pyridine. 0.28 g (1.1 mmol)D-proline-benzylester hydrochloride were added and stirring continued atroom temperature for 24 hours. The solvent was distilled off, theresidue taken up in acetoacetate and extracted with 2N HCl and brine.Drying with sodiumcarbonate, evaporation of the solvent andchromatography on silicagel with acetoacetate/hexane 1:1 yielded 0.094 g(R)-1-[4′-[(R)-2-carboxypyrrolidin-1-yl-carbonyl]-[2,2]-bithiazolyl-4-yl]pyrrolidine-2-carboxyolicacid benzyl ester.

[0245] MS m/e(%): 630 (M⁺, 24), 539 (17), 495 (44), 449 (51), 380 (25),329 (33), 313 (30), 223 (38), 194 (83), 180 (66), 145 (24), 137 (21), 91(100).

[0246] b)(R)-1-[4′-[(R)-2-Carboxy-pyrrolidin-1-yl-carbonyl]-[2,2]-bithiazolyl-4-yl]pyrrolidine-2-carboxylicacid

[0247] g (0.08 mmol)(R)-1-[4′-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl][2,2]-bithiazol-4-yl]pyrrolidine-2-carboxylicacid benzyl ester in 50 ml methanol were stirred with 5 ml 2Nsodiumhydoxide solution at room temperature for 64 hours. After additionof 2N hydrochloric acid until pH 1 the mixture was extracted withdichloromethane. The extracts were dried with sodiumsulfate andevaporated. Chromatography ocer silicagel withdichloromethane/acetone/formic acid 80/15/5 gave 0.04 g(R)-1-[4′-[(R)-2-Carboxy-pyrrolidin-1-yl-carbonyl]-[2,2]-bithiazolyl-4-yl]pyrrolidine-2-carboxylicacid as colorless solid.

[0248] MS-ISP: 451 (M+H)⁺.

EXAMPLE 21(R)-1-[[(R)-2-Carboxy-pyrrolidin-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0249] a) (R)-Pyrrolidine-2-carboxylic acid tert-butyl ester

[0250] The title compound was prepared according to a literatureprocedure (M. Thorsen, T. P. Andersen, U. Pedersen, B. Yde and S.-O.Lawesson, Tetrahedron, 41:5633-5636 (1985).

[0251] Starting from 25.0 g (217 mmol) D-proline, 27.52 g (74%) of(R)-pyrrolidine-2-carboxylic acid tert-butyl ester were obtained as acolorless oil.

[0252] a) (R)-Pyrrolidine-2-carboxylic acid tert-butyl ester

[0253] To a solution of 64.9 g (322 mmol) bromoacetyl bromide in 250 mldichloromethane at 0° C. was added dropwise a solution of 27.5 g (161mmol) (R)-pyrrolidine-2-carboxylic acid tert-butyl ester and 30 ml (177mmol) N-ethyidiisopropylamine in 150 ml dichloromethane within 40 min.The reaction mixture was allowed to warm to room temperature overnightand was poored into 600 ml of water. The organic phase was separated andthe water phase was extracted with 600 ml dichloromethane. The combinedorganic phases were washed with saturated sodium bicarbonate solutionand brine, dried (magnesium sulfate) and evaporated to yield 44.1 g(94%) of the title compound as a brown oil that crystallized uponstanding at room temperature.

[0254] Melting point 51.5-53.2° C.

[0255] c)(R)-1-[[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0256] To a solution of 34.3 g (200 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in350 ml dichloromethane at 0° C. were added dropwise 27.9 ml (200 mmol)triethylamine. After stirring for 45 min at this temperature, 17.8 g(200 mmol) bromoacetyl bromide were added dropwise. Stirring wascontinued at 0° C. for 3 h and 250 ml 1 N hydrochloric acid solutionwere added. The organic phase was separated and was washed withsaturated sodium bicarbonate solution and brine, dried (magnesiumsulfate) and evaporated to yield 45 g of a brown oil. Trituration withethyl acetate and cooling to −78° C. gave 7.1 g (9%) of a pale yellowsolid. Melting point 75.0-76.0° C. MS m/e (%): 405 (M+Na⁺, 11), 383(M+H⁺, 100).

[0257] d)(R)-1-[[(R)-2-Carboxy-pyrrolidin-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0258] A solution of 382 mg (1.0 mmol)(R)-1-[[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 300 mg (quantitative) ofRO-64-2799/000 as a pale yellow amorphous and hygroscopic solid whichstill contains trace amounts of trifluoroacetic acid.

[0259] MS m/e (%): 269 (M−H⁻, 4.5),113 (CF₃CO₂ ⁻, 100).

EXAMPLE 22(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0260] a)(R)-1-[[4-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0261] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 110 mg (1.0 mmol) hydroquinone in 2 ml dimethylformamide. Stirringwas continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 380mg (71%) of the title compound as a colorless oil.

[0262] MS m/e (%): 550 (M+NH₄ ⁺, 100), 477 (23), 421 (65).

[0263] b)(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0264] A solution of 350 mg (0.66 mmol)(R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 265 mg (96%) of the title compoundas a white powder.

[0265] MS m/e (%): 443 (M+Na⁺, 48), 438 (M+NH₄ ⁺, 39), 421 (M+H⁺, 100).

EXAMPLE 23(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2,3,5,6-tetrafluoro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0266] a)(R)-1-[[4-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2,3,5,6-tetrafluoro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0267] To a solution of 185 mg (1.65 mmol) potassium tert-butylate in 1ml dimethylformamide at room temperature was added dropwise a solutionof 137 mg (0.75 mmol) tetrafluorohydroquinone in 1 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 438 mg (1.50 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 2ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 4 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 87 mg(19%) of the title compound as a white foam. MS m/e (%): 622 (M+NH₄ ⁺,100), 549 (32), 493 (57).

[0268] b)(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2,3,5,6-tetrafluoro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0269] A solution of 80 mg (0.13 mmol)(R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2,3,5,6-tetrafluoro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 64 mg (96%) of the title compoundas a white powder.

[0270] MS m/e (%): 491 (M−H⁻, 100).

EXAMPLE 24(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-chloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0271] a)(R)-1-[[4-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-chloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0272] To a solution of 185 mg (1.65 mmol) potassium tert-butylate in 1ml dimethylformamide at room temperature was added dropwise a solutionof 108 mg (0.75 mmol) chlorohydroquinone in 1 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 438 mg (1.50 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 2ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 4 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 149mg (35%) of the title compound as a white foam.

[0273] MS m/e (%): 584 (M+NH₄ ⁺, 100), 511 (48), 455 (96).

[0274] b)(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-chloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0275] A solution of 140 mg (0.25 mmol)(R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-chloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 126 mg (quantitative) of the titlecompound as a white powder.

[0276] MS m/e (%): 453 (M−H⁻, 100).

EXAMPLE 25(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0277] a)(R)-1-[[4-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0278] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 140 mg (1.0 mmol) methoxyhydroquinone in 2 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 280mg (50%) of the title compound as a colorless oil.

[0279] MS m/e (%): 580 (M+NH₄ ⁺, 100), 563 (M+H⁺, 75), 507 (62), 451(67).

[0280] b)(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0281] A solution of 250 mg (0.44 mmol)(R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 188 mg (94%) of the title compoundas a white powder.

[0282] MS m/e (%): 473 (M+Na⁺, 45), 468 (M+NH₄ ⁺, 24), 451 (M+H⁺, 100).

EXAMPLE 26 Mixture of (R)-1-[(4-hydroxy-3- and-2-methoxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acid

[0283] a) Mixture of (R)-1-[(4-hydroxy-3- and-2-methoxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acid tert-butylester

[0284] The title compounds were formed as side products during thepreparation of(R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester. Isolation and purification byflash-chromatography gave 80 mg (23%) of RO-64-2915/000 as a colorlessoil.

[0285]¹H-NMR (CDCl₃), ppm): 1.41 (s, 2.4H), 1.45 (s, 6.6H), 1.81-2.32(m, 4H), 3.55-3.82 (m, 2H), 3.75 (s, 3H), 4.39-4.78 (m, 3H), 6.16-6.26(m, 1H) 6.40-6.43 (m, 1H), 6.67-6.74 (m, 1H).

[0286] b) Mixture of (R)-1-[(4-hydroxy-3- and-2-methoxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acid

[0287] To a solution of 80 mg (0.23 mmol) mixture of(R)-1-[(4-hydroxy-3- and-2-methoxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acid tert-butylester in 1 ml dichloromethane were added 5 ml of a 4 N solution ofhydrochloric acid in dioxane. After 24 h, the solvent was removed invacuo and the residue suspended in 10 ml ether. The resulting suspensionwas stirred overnight. Filtration and drying gave 65 mg (97%) of thetitle compound as a white powder.

[0288] MS m/e (%): 296 (M+H⁺, 100).

EXAMPLE 27(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0289] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0290] To a solution of 561 mg (5.0 mmol) potassium tert-butylate in 4ml dimethylformamide at room temperature was added dropwise a solutionof 275 mg (2.5 mmol) resorcinol in 4 ml dimethylformamide. Stirring wascontinued for 2-3 min and a solution of 1.46 mg (5.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 5ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 830mg (62%) of the title compound as a colorless oil.

[0291] MS m/e (%): 550 (M+NH₄ ⁺, 100), 533 (M+H⁺, 95), 477 (48), 421(95).

[0292] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0293] A solution of 750 mg (1.41 mmol)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 6 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 15 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 581 mg (98%) of the title compoundas a white powder.

[0294] MS m/e (%): 443 (M+Na⁺, 32), 438 (M+NH₄ ⁺, 20), 421 (M+H⁺, 100).

EXAMPLE 28 (R)-1-[(3-Hydroxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylicacid

[0295] a) (R)-1-[(3-Hydroxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0296] The title compound was formed as side product during thepreparation of(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester. Isolation and purification byflash-chromatography gave 120 mg (37%) of RO-64-2802/000 as a colorlessoil.

[0297] MS m/e (%): 344 (M+Na⁺, 9), 322 (M+H⁺, 73), 266 (100).

[0298] b) (R)-1-[(3-Hydroxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylicacid

[0299] To a solution of 120 mg (0.37 mmol)(R)-1-[(3-hydroxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acidtert-butyl ester in 1 ml dichloromethane were added 5 ml of a 4 Nsolution of hydrochloric acid in dioxane. After 3 d, the solvent wasremoved in vacuo and the residue suspended in 10 ml ether. The resultingsuspension was stirred overnight. Filtration and drying gave 95 mg (97%)of the title compound as a white powder.

[0300] MS m/e (%): 264 (M−H⁻, 100).

EXAMPLE 29(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0301] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0302] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 124 mg (1.0 mmol) 2,6-dihydroxytoluene in 2 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 335mg (61%) of the title compound as a colorless oil.

[0303] MS m/e (%): 564 (M+NH₄ ⁺, 100), 491 (27), 435 (71).

[0304] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0305] A solution of 300 mg (0.55 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 226 mg (95%) of the title compoundas a white powder.

[0306] MS m/e (%): 457 (M+Na⁺, 54), 452 (M+NH₄ ⁺, 55), 435 (M+H⁺, 100).

EXAMPLE 30(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0307] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0308] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 140 mg (1.0 mmol) 5-methoxyresorcinol in 2 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 407mg (72%) of the title compound as a colorless oil.

[0309] MS m/e (%): 580 (M+NH₄ ⁺, 98), 563 (M+H⁺, 100), 507 (54), 451(95).

[0310] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0311] A solution of 370 mg (0.66 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 287 mg (97%) of the title compoundas a white powder.

[0312] MS m/e (%): 473 (M+Na⁺, 45), 468 (M+NH₄ ⁺, 30), 451 (M+H⁺, 100).

EXAMPLE 31(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxycarbonyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0313] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxycarbonyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0314] To a solution of 595 mg (5.3 mmol) potassium tert-butylate in 4ml dimethylformamide at room temperature was added dropwise a solutionof 420 mg (2.5 mmol) 3,5-dihydroxybenzoate in 4 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 1.46 mg (5.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 5ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 2 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 1.01g (68%) of the title compound as a colorless oil.

[0315] MS m/e (%): 608 (M+NH₄ ⁺, 92), 591 (M+H⁺, 48), 535 (41), 479(100).

[0316] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxycarbonyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0317] A solution of 710 mg (1.2 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxycarbonyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 10 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 20 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 540 mg (94%) of the title compoundas a white powder.

[0318] MS m/e (%): 477 (M−H⁻, 100).

EXAMPLE 32(R)-1-[[3-Carboxy-5-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0319] To 10 ml of a 0.5 N lithium hydroxide solution inmethanol/water=3:1 were added 100 mg (0.2 mmol) of(R)-1-[[3-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxycarbonyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid. The solution was allowed to stand at room temperature for 24 h.The mixture was adjusted to pH 6 by dropwise addition of hydrochloricacid solution and lyophilized to give 800 mg of a white powder. Theproduct was isolated by chromatography using an ion exchange resin(Dowex). Lyophilization gave 20 mg (22%) of the title compound as awhite powder.

[0320] MS m/e (%): 487 (M+Na⁺, 61), 482 (M+NH₄ ⁺, 54), 465 (M+H⁺, 100).

EXAMPLE 33

[0321] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-cyano-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0322] To a solution of 1.35 g (10 mmol) 3,5-dihydroxybenzonitrile and5.84 g (20 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 25 ml dimethylformamide at room temperature wereadded 7 g anhydrous potassium carbonate. After stirring for additional20 h, the potassium salts were filtered off and the solvent was removedin vacuo. The residue was purified by flash-chromatography to yield 4.77g (86%) of the title compound as a colorless foam.

[0323] MS m/e (%): 575 (M+NH₄ ⁺, 100), 558 (M+H⁺, 42), 502 (35), 446(85).

[0324] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-cyano-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0325] A solution of 280 mg (0.5 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-cyano-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 280 mg (72%) of the title compoundas a white powder.

[0326] MS m/e (%): 444 (M−H⁻, 100).

EXAMPLE 34(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-1H-tetrazol-5-yl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0327] To a solution of 110 mg (0.2 mmol)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-cyano-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 10 ml 1,2-dimethoxyethane were added 200 mg(0.6 mmol) tributyltin azide. The mixture was heated at reflux for 3days. After cooling to room temperature, 1.4 g of gaseous hydrochloricacid were bubbled into the solution to obtain a 4 N hydrochloric acidsolution in 1,2-dimethoxyethane and stirring was continued for 12 h. Thesolvent was removed in vacuo and the oily residue was triturated withether to give 61 mg (92%) of the title compound as a pale yellowamorphous solid.

[0328] MS m/e (%): 511 (M+Na⁺, 41), 506 (M+NH₄ ⁺, 32), 489 (M+H⁺, 100).

EXAMPLE 35(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-hydroxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0329] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-hydroxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0330] To a solution of 95 mg (0.75 mmol) phloroglucinol and 438 mg (1.5mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl esterin 2 ml dimethylformamide at room temperature were added 520 mganhydrous potassium carbonate. After stirring overnight, the potassiumsalts were filtered off and the solvent was removed in vacuo. Theresidue was purified by flash-chromatography to yield 50 mg (12%) of thetitle compound as a white foam.

[0331] MS m/e (%): 566 (M+NH₄ ⁺, 96), 549 (M+H⁺, 88), 493 (47), 437(100).

[0332] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-hydroxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0333] A solution of 46 mg (0.084 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-hydroxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 5 ml ether. The resulting suspension was stirred overnight.Filtration and drying gave 35 mg (96%) of the title compound as a lightbrown powder.

[0334] MS m/e (%): 435 (M−H⁻, 100).

EXAMPLE 36(R)-1-[[3,5-Bis-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0335] a)(R)-1-[[3,5-Bis-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0336] To a solution of 95 mg (0.75 mmol) phloroglucinol and 220 mg(0.75 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butylester in 2 ml dimethylformamide at room temperature were added 520 mganhydrous potassium carbonate. After 2 h and 6 h stirring at roomtemperature, 220 mg (0.75 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester wereadded (per addition) and stirring was continued for 18 h. The potassiumsalts were filtered off and the solvent was removed in vacuo. Theresidue was purified by flash-chromatography to yield 465 mg (82%) ofthe title compound as a colorless foam.

[0337] MS m/e (%): 777 (M+NH₄ ⁺, 100), 760 (M+H⁺, 4), 704 (11), 648(22), 592 (22).

[0338] b)(R)-1-[[3,5-Bis-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0339] A solution of 350 mg (0.47 mmol)(R)-1-[[3,5-bis-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 254 mg (92%) of the title compoundas a light brown powder.

[0340] MS m/e (%): 614 (M+Na⁺, 73), 609 (M+NH₄ ⁺, 100), 592 (M+H⁺, 56).

EXAMPLE 37 Mixture of (E)- and(Z)-(R)-1-[[3-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(N-hydroxycarbamimidoyl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0341] a) Mixture of (E)- and(Z)-(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(N-hydroxycarbamimidoyl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acidtert-butyl ester

[0342] To a solution of 1.25 g (17.9 mmol) hydroxylamine hydrochloridein 6 ml dimethyl sulfoxide were added 1.82 g (18 mmol) triethylamine. Aninsoluble material was filtered off and was washed with 5 mltetrahydrofuran. The filtrate was concentrated in vacuo at 100 mbar toremove tetrahydrofuran and 2.0 g (3.59 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-cyano-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester were added. After stirring for 20 h at 75° C., thereaction mixture was diluted with water and extracted with ethylacetate. The organic solution was extracted with 1 N hydrochloric acidsolution. The aqueous solution was adjusted to pH 10 with 1 N sodiumhydroxide solution and extracted with ethyl acetate. The organicsolution was washed with water, dried (sodium sulfate) and evaporated togive 1.74 g of the title compound as a colorless foam.

[0343] MS m/e (%): 613 (M+Na⁺, 7), 591 (M+H⁺, 100), 535 (21), 479 (15).

[0344] b) Mixture of (E)- and(Z)-(R)-1-[[3-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(N-hydroxycarbamimidoyl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0345] A solution of 120 mg (0.2 mmol) mixture of (E)- and(Z)-(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(N-hydroxycarbamimidoyl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acidtert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h atroom temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 96 mg (quantitative) of the titlecompound as a light brown powder.

[0346] MS m/e (%): 501 (M+Na⁺, 31), 479 (M+H⁺, 100).

EXAMPLE 38(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0347] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0348] To an ice-cooled solution of 300 mg (0.51 mmol) mixture of (E)-and(Z)-(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(N-hydroxycarbamimidoyl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester and 43 mg (0.55 mmol) pyridine in 2 mldimethylformamide were added dropwise 200 mg (0.51 mmol) 2-ethylhexylchloroformate. The mixture was stirred at 0° C. for 30 min, diluted withwater and extracted with ethyl acetate. The organic phase was dried(sodium sulfate) evaporated and the oily residue was dissolved in 20 mltoluene. After 16 h stirring at room temperature, the toluene solutionwas washed with brine, dried (sodium sulfate) and filtered over silicagel to give 280 mg (89%) of the title compound as a viscous oil.

[0349] MS m/e (%): 639 (M+Na⁺, 51), 634 (M+NH₄ ⁺, 100), 617 (M+H⁺, 14),561 (40), 505 (79).

[0350] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0351] A solution of 220 mg (0.36 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 135 mg (74%) of the title compoundas a light brown powder.

[0352] MS m/e (%): 527 (M+Na⁺, 73), 522 (M+NH₄ ⁺, 75), 505 (M+H⁺, 100).

EXAMPLE 39(R)-1-[[3-[2-[(R)-2-Carbonxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(2-oxo-2,3-dihydro-[1,2,3,5]oxathiadiazol-4-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid (config. of S-oxide R:S=1:1)

[0353] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(2-oxo-2,3-dihydro-[1,2,3,5]oxathiadiazol-4-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester (config. of S-oxide R:S=1:1)

[0354] To an ice-cooled solution of 300 mg (0.51 mmol) mixture of (E)-and(Z)-(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(N-hydroxycarbamimidoyl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester and 80 mg (1 mmol) pyridine in 2 mldichloromethane were added dropwise 60 mg (0.51 mmol) thionyl chloride(dissolved in 0.3 ml dichloromethane). The mixture was stirred at 0° C.for 45 min, diluted with dichloromethane, washed with water, dried(sodium sulfate) and evaporated. Flash-chromatography gave 190 mg (59%)of the title compound as a semi-solid liquid. MS m/e (%): 659 (M+Na⁺,14), 654 (M+NH₄ ⁺, 100), 637 (M+H⁺, 11), 581 (14), 525 (74).

[0355] b)(R)-1-[[3-[2-[(R)-2-Carbonxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(2-oxo-2,3-dihydro-[1,2,3,5]oxathiadiazol-4-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid (config. of S-oxide R:S=1:1)

[0356] A solution of 165 mg (0.26 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(2-oxo-2,3-dihydro-[1,2,3,5]oxathiadiazol-4-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acidtert-butyl ester (config. of S-oxide R:S=1:1) in 1.5 ml trifluoroaceticacid was stirred for 4 h at room temperature. The solvent was removed invacuo and the residue suspended in 10 ml ether. The resulting suspensionwas stirred overnight. Filtration and drying gave 115 mg (85%) of thetitle compound as a light brown powder.

[0357] MS m/e (%): 547 (M+Na⁺, 65), 542 (M+NH₄ ⁺, 86), 525 (M+H⁺, 100).

EXAMPLE 40(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-tert-butylsulfanyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0358] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-thioso-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0359] A mixture of 515 mg (0.87 mmol) mixture of (E)- and(Z)-(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(N-hydroxycarbamimidoyl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acidtert-butyl ester, 177 mg (0.94 mmol) 1,1′-thiocarbonyldiimidazole and530 mg (3.5 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 mlacetonitrile was stirred at room temperature for 4 h. The mixture wasconcentrated in in vacuo, diluted with water, adjusted to pH 4-5 with 1N hydrochloric acid solution and extracted with ethyl acetate. Theextract was concentrated again, the residue was dissolved in 100 ml 1 Nsodium hydroxide solution and washed with ether. The aqueous solutionwas adjusted to pH 4 with 1 N hydrochloric acid solution and wasextracted with ethyl acetate. The organic phase was washed with water,dried (sodium sulfate) and was evaporated to give 490 mg (89%) of thetitle compound as a pale brown foam.

[0360] MS m/e (%): 655 (M+Na⁺, 35), 650 (M+NH₄ ⁺, 100), 633 (M+H⁺, 14),577 (31), 521 (52).

[0361] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-tert-butylsulfanyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0362] A solution of 315 mg (0.5 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 160 mg (57%) of the title compoundas a white powder.

[0363] MS m/e (%): 599 (M+Na⁺, 54), 594 (M+NH₄ ⁺, 71), 577 (M+H⁺, 100),521 (37).

EXAMPLE 41(R)-1-[[2-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0364] a)(R)-1-[[2-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0365] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 140 mg (1.0 mmol) pyrogallol-1-methyl ether in 2 mldimethylformamide. Stirring was continued for 2-3 min and a solution of584 mg (2.0 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 4 ml dimethylformamide was added within 1-2 min. Thereaction mixture was stirred for additional 3 h at room temperature. Thesolvent was removed in vacuo and the residue purified byflash-chromatography to yield 375 mg (67%) of the title compound as acolorless oil.

[0366] MS m/e (%): 580 (M+NH₄ ⁺, 14), 563 (M+H⁺, 100), 507 (14), 451(12).

[0367] b)(R)-1-[[2-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0368] A solution of 345 mg (0.61 mmol)(R)-1-[[2-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methoxy-phenoxyl-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 265 mg (96%) of the title compoundas a white powder.

[0369] MS m/e (%): 473 (M+Na⁺, 54), 451 (M+H⁺, 100).

EXAMPLE 42(R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0370] a)(R)-1-[[2-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0371] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 124 mg (1.0 mmol) 3-methylcatechol in 2 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 356mg (65%) of the title compound as a colorless oil.

[0372] MS m/e (%): 547 (M+H⁺, 100), 491 (14), 435 (17).

[0373] b)(R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0374] A solution of 325 mg (0.60 mmol)(R)-1-[[2-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 235 mg (91%) of the title compoundas a white powder.

[0375] MS m/e (%): 457 (M+Na⁺, 59), 435 (M+H⁺, 100).

EXAMPLE 43(R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-3,4,5,6-tetrachloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0376] a)(R)-1-[[2-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3,4,5,6-tetrachloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0377] To a solution of 185 mg (1.65 mmol) potassium tert-butylate in 1ml dimethylformamide at room temperature was added dropwise a solutionof 186 mg (0.75 mmol) tetrachlorocatechol in 1 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 438 mg (1.50 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 2ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 4 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 229mg (45%) of the title compound as a white foam.

[0378] MS m/e (%): 671 (M+H⁺, 100), 615 (19), 559 (14).

[0379] b)(R)-1-[[2-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-3,4,5,6-tetrachloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0380] A solution of 220 mg (0.34 mmol)(R)-1-[[2-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3,4,5,6-tetrachloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 172 mg (94%) of the title compoundas a white powder.

[0381] MS m/e (%): 559 (M−H⁻, 100).

EXAMPLE 44R)-1-[[6-[2-[(R)-2-Carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]pyrrolidine-2-carboxylicacid

[0382] a)(R)-1-[[6-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0383] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 160 mg (1.0 mmol) 2,6-dihydroxynaphthalene in 2 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 120mg (21%) of the title compound as a white solid.

[0384] MS m/e (%): 605 (M+Na⁺, 14), 600 (M+NH₄ ⁺, 92), 583 (M+H⁺, 5),527 (32), 471 (100).

[0385] b)R)-1-[[6-[2-[(R)-2-Carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0386] A solution of 75 mg (0.13 mmol)(R)-1-[[6-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 18h at room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 60 mg (98%) of the title compoundas a white powder.

[0387] MS m/e (%): 493 (M+Na⁺, 58), 488 (M+NH₄ ⁺, 33), 471 (M+H⁺, 100).

EXAMPLE 45(R)-1-[[5-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0388] a)(R)-1-[[5-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0389] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 160 mg (1.0 mmol) 1,5-dihydroxynaphthalene in 2 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 470mg (81%) of the title compound as a pale yellow foam.

[0390] MS m/e (%): 605 (M+Na⁺, 10), 600 (M+NH₄ ⁺, 100), 527 (20), 471(63).

[0391] b)(R)-1-[[5-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0392] A solution of 290 mg (0.5 mmol)(R)-1-[[5-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 230 mg (98%) of the title compoundas a white powder.

[0393] MS m/e (%): 493 (M+Na⁺, 45), 488 (M+NH₄ ⁺, 37), 471 (M+H⁺, 100).

EXAMPLE 46(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0394] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0395] To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2ml dimethylformamide at room temperature was added dropwise a solutionof 160 mg (1.0 mmol) 2,3-dihydroxynaphthalene in 2 ml dimethylformamide.Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4ml dimethylformamide was added within 1-2 min. The reaction mixture wasstirred for additional 3 h at room temperature. The solvent was removedin vacuo and the residue purified by flash-chromatography to yield 310mg (53%) of the title compound as a colorless oil.

[0396] MS m/e (%): 605 (M+Na⁺, 27), 600 (M+NH₄ ⁺, 16), 583 (M+H⁺, 100),527 (16), 471 (24).

[0397] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0398] A solution of 230 mg (0.4 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 180 mg (96%) of the title compoundas a white powder.

[0399] MS m/e (%): 469 (M−H⁻, 100).

EXAMPLE 47(R)-1-[[2′-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-biphenyl-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0400] a)(R)-1-[[2′-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-biphenyl-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0401] To a solution of 160 mg (1.44 mmol) potassium tert-butylate in1.6 ml dimethylformamide at room temperature was added dropwise asolution of 127 mg (0.69 mmol) 2,2′-dihydroxybiphenyl in 1 mldimethylformamide. Stirring was continued for 2-3 min and a solution of400 mg (1.37 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 4 ml dimethylformamide was added within 1-2 min. Thereaction mixture was stirred overnight at room temperature. The solventwas removed in vacuo and the residue purified by flash-chromatography toyield 84 mg (20%) of the title compound as a light brown oil.

[0402] MS m/e (%): 631 (M+Na⁺, 22), 626 (M+NH₄ ⁺, 100), 609 (M+H⁺, 16).

[0403] b)(R)-1-[[2′-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-biphenyl-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0404] A solution of 87 mg (0.14 mmol)(R)-1-[[2′-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-biphenyl-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 31 mg (44%) of the title compoundas a light brown powder.

[0405] MS m/e (%): 519 (M+Na⁺, 62), 497 (M+H⁺, 100).

EXAMPLE 48(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0406] a)(R)-1-[[4-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0407] To a solution of 160 mg (1.44 mmol) potassium tert-butylate in1.6 ml dimethylformamide at room temperature was added dropwise asolution of 116 mg (0.69 mmol) 1,4-naphthoquinone in 1 mldimethylformamide. Stirring was continued for 2-3 min and a solution of400 mg (1.37 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 4 ml dimethylformamide was added within 1-2 min. Thereaction mixture was stirred overnight at room temperature. The solventwas removed in vacuo and the residue purified by flash-chromatography toyield 269 mg (67%) of the title compound as a light brown foam.

[0408] MS m/e (%): 600 (M+NH₄ ⁺, 100).

[0409] b)(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0410] A solution of 172 mg (0.30 mmol)(R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 140 mg (quantitative) of the titlecompound as a light brown powder.

[0411] MS m/e (%): 469 (M−H⁻, 100).

EXAMPLE 49(R)-1-[[7-[2-[(R)-2-Carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0412] a)(R)-1-[[7-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0413] To a solution of 110 mg (0.69 mmol) 2,7-dihydroxynaphthalene and400 mg (1.37 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 1.5 ml dimethylformamide at room temperature wereadded 480 mg anhydrous potassium carbonate. After stirring foradditional 20 h, the potassium salts were filtered off and the solventwas removed in vacuo. The residue was purified by flash-chromatographyto yield 296 mg (74%) of the title compound as a white foam.

[0414] MS m/e (%): 600 (M+NH₄ ⁺, 100), 527 (25), 471 (99).

[0415] b)(R)-1-[[7-[2-[(R)-2-Carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0416] A solution of 272 mg (0.47 mmol)(R)-1-[[7-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 209 mg (95%) of the title compoundas a white powder.

[0417] MS m/e (%): 493 (M+Na⁺, 48), 488 (M+NH₄ ⁺, 23), 471 (M+H⁺, 100).

EXAMPLE 50(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:2)

[0418] a)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0419] To a solution of 75 mg (0.69 mmol) 1,3-phenylenediamine and 400mg (1.37 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 3 ml dichloromethane at room temperature were added0.21 ml (1.5 mmol) triethylamine. The reaction mixture was stirredovernight at room temperature. The organic phase was washed with 1 Nsodium carbonate solution and brine, dried (sodium sulfate) andevaporated. The residue was purified by flash-chromatography to yield285 mg (78%) of the title compound as a light brown foam.

[0420] MS m/e (%): 553 (M+Na⁺, 15), 531 (M+H⁺, 100), 475 (20), 419 (10).

[0421] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:2)

[0422] A solution of 170 mg (0.32 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 130 mg (63%) of the title compoundas a brown foam.

[0423] MS m/e (%): 417 (M−H⁻, 100).

EXAMPLE 51(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:2)

[0424] a)(R)-1-[[4-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0425] To a solution of 75 mg (0.69 mmol) 1,4-phenylenediamine and 400mg (1.37 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 4 ml tetrahydrofuran at room temperature were added190 mg anhydrous potassium carbonate. The reaction mixture was stirredovernight at 40° C. The potassium salts were filtered off and thesolvent was removed in vacuo. The residue was purified byflash-chromatography to yield 180 mg (50%) of the title compound as abrown foam.

[0426] MS m/e (%): 553 (M+Na⁺, 26), 531 (M+H⁺, 100).

[0427] b)(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:2)

[0428] A solution of 168 mg (0.32 mmol)(R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed, the residue suspended intoluene and the solvent removed again to eliminate excesstrifluoroacetic acid. The residue was re-suspended in 10 ml ether. Theresulting suspension was stirred overnight. Filtration and drying gave160 mg (78%) of the title compound as a brown foam.

[0429] MS m/e (%): 417 (M−H⁻, 100).

EXAMPLE 52(R)-1-[[[2-[(R)-2-Carbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-butyl-amino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1

[0430] a)(R)-1-[[[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-butyl-amino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0431] To a solution of 136 mg (1.86 mmol) butylamine and 995 mg (3.40mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl esterin 4 ml dichloromethane at room temperature were added 0.52 ml (3.74mmol) triethylamine. The suspension was stirred overnight at roomtemperature. The organic phase was washed with 1 N sodium carbonatesolution and brine, dried (sodium sulfate) and evaporated. The residuewas purified by flash-chromatography to yield 830 mg (98%) of the titlecompound as a light brown oil.

[0432] MS m/e (%): 524 (2M+Ni⁺, 37), 496 (M+H⁺, 100), 468 (2), 440 (7).

[0433] b)(R)-1-[[[2-[(R)-2-Carbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-butyl-amino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0434] A solution of 50 mg (0.1 mmol)(R)-1-[[[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-butyl-amino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 0.2 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 46 mg (92%) of the title compoundas a light brown powder.

[0435] MS m/e (%): 382 (M−H⁻, 100).

EXAMPLE 53(R)-1-[[[2-[(R)-2-Carbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-(2-methoxy-ethyl)-amino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0436] a)(R)-1-[[[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-(2-methoxy-ethyl)-amino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0437] To a solution of 137 mg (1.83 mmol) 2-methoxyethylamine and 970mg (3.33 mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester in 4 ml dichloromethane at room temperature were added0.51 ml (3.66 mmol) triethylamine. The suspension was stirred overnightat room temperature. The organic phase was washed with 1 N sodiumcarbonate solution and brine, dried (sodium sulfate) and evaporated. Theresidue was purified by flash-chromatography to yield 397 mg (48%) ofthe title compound as a light brown oil.

[0438] MS m/e (%): 520 (M+Na⁺, 50), 498 (M+H⁺, 100).

[0439] b.(R)-1-[[[2-[(R)-2-Carbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-(2-methoxy-ethyl)amino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0440] A solution of 367 mg (0.74 mmol)(R)-1-[[[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-(2-methoxy-ethyl)-amino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 350 mg (95%) of the title compoundas a light brown foam.

[0441] MS m/e (%): 384 (M−H⁻, 100).

EXAMPLE 54(R)-1-[[Benzyl-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-amino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0442] a)(R)-1-[[Benzyl-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-amino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0443] To a solution of 104 mg (0.97 mmol) benzylamine and 514 mg (1.76mmol) (R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl esterin 5 ml dichloromethane at room temperature were added 0.27 ml (1.94mmol) triethylamine. The suspension was stirred overnight at roomtemperature. The organic phase was washed with 1 N sodium carbonatesolution and brine, dried (sodium sulfate) and evaporated. The residuewas purified by flash-chromatography to yield 270 mg (58%) of the titlecompound as a light brown oil.

[0444] MS m/e (%): 552 (M+Na⁺, 12), 530 (M+H⁺, 100).

[0445] b)(R)-1-[[Benzyl-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-amino]-acetyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0446] A solution of 200 mg (0.38 mmol)(R)-1-[[Benzyl-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-amino]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 3 hat room temperature. The solvent was removed in vacuo and the residuesuspended in 10 ml ether. The resulting suspension was stirredovernight. Filtration and drying gave 189 mg (94%) of the title compoundas white crystals.

[0447] MS m/e (%): 440 (M+Na⁺, 16), 418 (M+H⁺, 100).

EXAMPLE 55(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-1,3-dibutyl-ureido]-acetyl]-pyrrolidine-2-carboxylicacid

[0448] a) (R)-1-Butylaminoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester

[0449] To a solution of 1.58 ml (16 mmol) butylamine in 1 mldichloromethane was added dropwise a solution of 470 mg (1.6 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 2ml dichloromethane at room temperature. The suspension was stirredovernight. The organic phase was washed with 1 N sodium carbonatesolution and brine, dried (sodium sulfate) and evaporated. The residuewas purified by flash-chromatography to yield 370 mg (81%) of the titlecompound as a light brown oil.

[0450] MS m/e (%): 285 (M+H⁺, 100).

[0451] b)(R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-1,3-dibutyl-ureido]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0452] To a solution of 165 mg (0.58 mmol)(R)-1-butylaminoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in5 ml toluene were added 305 mg anhydrous sodium carbonate. Thesuspension was evaporated to dryness and the residue was re-suspended in2 ml tetrahydrofuran. Then, 1.4 ml (2.88 mmol) of a phosgene solution(20% in toluene) were added and stirring was continued for 6 h at 50° C.The sodium salts were filtered off and washed with tetrahydrofuran. Thefiltrate was evaporated and 165 mg (0.58 mmol) RO-64-2576/000 dissolvedin 2 ml tetrahydrofuran and 305 mg anhydrous sodium carbonate were addedagain. After stirring overnight at 50° C., the organic phase was washedwith 1 N hydrochloric acid solution, dried (magnesium sulfate) andevaporated to give 330 mg (91%) of the tiltle compound as a light brownpowder.

[0453] MS m/e (%): 617 (M+Na⁺, 19), 595 (M+H⁺, 100).

[0454] c)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-1,3-dibutyl-ureido]-acetyl]-pyrrolidine-2-carboxylicacid

[0455] A solution of 278 mg (0.47 mmol)(R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-1,3-dibutyl-ureido]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 4 hat room temperature. The solvent was removed in vacuo and the residuewas dried to give 167 mg (74%) of the title compound as brown foam.

[0456] MS m/e (%): 505 (M+Na⁺, 11), 487 (33), 483 (M+H⁺, 33),465 (100).

EXAMPLE 56(R)-1-[[1,3-Dibenzyl-3-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-ureido]-acetyl]-pyrrolidine-2-carboxylicacid

[0457] a) (R)-1-Benzylaminoacetyl-pyrrolidine-2-carboxylic acidtert-butyl ester

[0458] To a solution of 1.25 ml (11.4 mmol) benzylamine in 1 mldichloromethane was added dropwise a solution of 335 mg (1.14 mmol)(R)-(1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 2ml dichloromethane at 0° C. The suspension was stirred for 4 h at thistemperature. The organic phase was washed with 1 N sodium carbonatesolution and brine, dried (sodium sulfate) and evaporated. The residuewas purified by flash-chromatography to yield 312 mg (86%) of the titlecompound as an amorphous solid.

[0459] MS m/e (%): 319 (M+H⁺, 100).

[0460] b)(R)-1-[[1,3-Dibenzyl-3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-ureido]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0461] To a solution of 233 mg (0.73 mmol)(R)-1-benzylaminoacetyl-pyrrolidine-2-carboxylic acid tert-butyl esterin 2 ml toluene at room temperature were added 0.20 ml (1.34 mmol)triethylamine. Over a period of 3 h, 0.30 ml (0.70 mmol) of a phosgenesolution (20% in toluene) were added in 6 portions and stirring wascontinued for 3 h at room temperature. The organic phase was washed with1 N hydrochloric acid solution, 1 N sodium carbonate solution and brine,dried (magnesium sulfate) and evaporated. The residue was purified byflash-chromatography to give 245 mg (50%) of the title compound as alight yellow oil.

[0462] MS m/e (%): 685 (M+Na⁺, 28), 680 (M+NH₄ ⁺, 100), 663 (M+H⁺, 30).

[0463] c)(R)-1-[[1,3-Dibenzyl-3-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-ureido]-acetyl]-pyrrolidine-2-carboxylicacid

[0464] A solution of 220 mg (0.33 mmol)(R)-1-[[1,3-Dibenzyl-3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-ureido]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml 4 N hydrochloric acid solution in dioxanewas stirred for 5 h at room temperature. The product was extracted with1 N sodium hydroxide solution, the basic extract was acidified with 1 Nhydrochloric acid solution to pH 4 and the product extracted with ethylacetate. The organic phase was dried (magnesium sulfate) and evaporatedto give 74 mg (41%) of the title compound as a brown oil.

[0465] MS m/e (%): 549 (M−H⁻, 100).

EXAMPLE 57 (R)-1-Benzylaminoacetyl-pyrrolidine-2-carboxylic acid

[0466] The title compound was formed via urea cleavage as side productduring the preparation of(R)-1-[[1,3-Dibenzyl-3-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-ureido]-acetyl]-pyrrolidine-2-carboxylicacid. It was isolated from the acidified aqueous solution as follows.The water phase was concentrated and the residue was suspended in2-propanol. Inorganic salts were filtered off over celite. Evaporationand drying gave 78 mg (45%) of(R)-1-benzylaminoacetyl-pyrrolidine-2-carboxylic acid as a colorlessfoam.

[0467] MS m/e (%): 261 (M−H⁻, 100).

[0468] The following general procedures are used in the Examples thatfollow:

[0469] General Procedure A: EDC Coupling Reaction

[0470] To a stirred solution of D-proline benzyl ester hydrochloride (2equiv.), a dicarboxylic acid (1 equiv.), N-methylmorpholine (6 equiv.)and hydroxybenzotriazole (2 equiv.) in dichloromethane at 0° C. wasadded N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2equiv.) and stirring continued at 0° C. for 2 h and then at roomtemperature for 16 h. The reaction mixture was then washed sequentiallywith 1 M hydrochloric acid, saturated sodium bicarbonate solution andfinally with saturated brine, and the aqueous phases back-extracted withdichloromethane. The combined organic extracts were dried over sodiumsulphate and concentrated in vacuo. Purification by flash chromatographyon kieselgel then afforded the title compound.

[0471] General Procedure B: Hydrogenolysis of Benzyl Ester

[0472] A solution of the benzyl ester in isopropanol was stirred with 5wt % of 10% palladium on charcoal under 1 atm of hydrogen for 16 h atroom temperature. After filtration to remove the catalyst, the reactionmixture was concentrated in vacuo and azeotroped three times withchloroform on a rotary evaporator to remove last traces of isopropanol.The resulting product (often a viscous oil, semi-solid or foam) wastriturated in ether and then dried in vacuo (10 mbar) at 50° C. for 16h.

EXAMPLE 58(R)-1-[5-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,4-dimethyl-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0473] a)(R)-1-[5-[(R)-2-Benzyloxymethyl-pyrrolidin-1-yl]-2,4-dimethyl-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers)

[0474] Using General Procedure A with 6.05 g (25 mmol) D-Proline benzylester hydrochloride and 2.0 g (12.5 mmol) 2,4-dimethylglutaric acidafforded, after flash chromatography (EtOAc), 4.3 g (64%) of the titlecompound as a light yellow oil. MS m/e (%): 535 (M+H⁺, 100).

[0475] b)(R)-1-[5-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,4-dimethyl-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0476] Using General Procedure B with 4.30 g (8.05 mmol)(R)-1-[5-[(R)-2-benzyloxymethyl-pyrrolidin-1-yl]-2,4-dimethyl-5-oxo-pentanoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers) afforded 2.58 g (91%) ofthe title compound as a white foam. MS m/e (%): 355 (M+H⁺, 100).

EXAMPLE 59(R)-1-[4-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,3-dimethyl-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0477] a)(R)-1-[4-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,3-dimethyl-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers)

[0478] Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzylester hydrochloride and 600 mg (4.1 mmol) 2,3-dimethylsuccinic acidafforded, after flash chromatography (EtOAc), 1.45 g (69%) of the titlecompound as a colorless oil. MS m/e (%): 521 (M+H⁺, 100).

[0479] b)(R)-1-[4-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,3-dimethyl-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0480] Using General Procedure B with 1.45 g (2.78 mmol)(R)-1-[4-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,3-dimethyl-4-oxo-butyryl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers) afforded 780 mg (80%) ofthe title compound as a white foam. MS m/e (%): 341 (M+H⁺, 100).

EXAMPLE 60(R)-1-[trans-4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid

[0481] a)(R)-1-[trans-4-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0482] Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzylester hydrochloride and 700 mg (4.1 mmol)trans-cyclohexane-1,4-dicarboxylic acid afforded, after flashchromatography (EtOAc), 1.67 g (76%) of the title compound as acolorless oil. MS m/e (%): 547 (M+H⁺, 100).

[0483] b)(R)-1-[trans-4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid

[0484] Using General Procedure B with 1.61 g (2.95 mmol)(R)-1-[trans-4-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 1.07 g (99%) of the title compound as a whitefoam. MS m/e (%): 367 (M+H⁺, 100).

EXAMPLE 61(R)-1-[cis-4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid

[0485] a)(R)-1-[cis-4-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0486] Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzylester hydrochloride and 700 mg (4.1 mmol)cis-cyclohexane-1,4-dicarboxylic acid afforded, after flashchromatography (EtOAc), 2.0 g (91%) of the title compound as a colorlessoil. MS m/e (%): 547 (M+H⁺, 100).

[0487] b)(R)-1-[cis-4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid

[0488] Using General Procedure B with 2.0 g (3.66 mmol)(R)-1-[cis-4-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 930 mg (69%) of the title compound as a whitefoam. MS m/e (%): 365 ([M−H]⁻, 100).

EXAMPLE 62(R)-1-[3-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0489] a)(R)-1-[3-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers)

[0490] Using General Procedure A with 5.6 g (23.2 mmol) D-Proline benzylester hydrochloride and 2.0 g (11.6 mmol) cyclohexane-1,3-dicarboxylicacid afforded, after flash chromatography (EtOAc), 4.4 g (70%) of thetitle compound as a colorless oil. MS m/e (%): 547 (M+H⁺, 100).

[0491] b)(R)-1-[3-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0492] Using General Procedure B with 4.4 g (8.05 mmol)(R)-1-[3-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers) afforded 2.9 g (98%) ofthe title compound as a white foam. MS m/e (%): 367 (M+H⁺, 100).

EXAMPLE 63 Mixture of (R)-1-[(1R,2R)- and-[(1S,2S)-2-[(R)-2-carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid

[0493] a) Mixture of (R)-1-[(1R,2R)- and[(1S,2S)-2-[(R)-2-benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl

[0494] Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzylester hydrochloride and 700 mg (4.1 mmol)trans-cyclohexane-1,2-dicarboxylic acid afforded, after flashchromatography (EtOAc), 1.36 g (62%) of the title compound as acolorless oil. MS m/e (%): 547 (M+H⁺, 100).

[0495] b) Mixture of (R)-1-[(1R,2R)- and-[(1S,2S)-2-[(R)-2-carboxy-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid

[0496] Using General Procedure B with 1.36 g (2.48 mmol) mixture of(R)-1-[(1 R,2R)- and[(1S,2S)-2-[(R)-2-benzyloxycarbonyl-pyrrolidine-1-carbonyl]-cyclohexanecarbonyl]-pyrrolidine-2-carboxylicacid benzyl afforded 900 mg (99%) of the title compound as a white foam.MS m/e (%): 367 (M+H⁺, 100).

EXAMPLE 64(R)-1-[[2,5-Dihydroxy-4-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid

[0497] a)(R)-1-[[4-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-2,5-dihydroxy-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0498] Using General Procedure A with 10.7 g (44.2 mmol) D-Prolinebenzyl ester hydrochloride and 5.0 g (22.1 mmol)2,5-dihydroxy-1,4-phenylenediacetic acid afforded, after flashchromatography (gradient: 70-100% EtOAc/hexane), 3.17 g (24%) of thetitle compound as a colorless foam. MS m/e (%): 601 (M+H⁺, 100).

[0499] b)(R)-1-[[2,5-Dihydroxy-4-[2-[(R)-2-carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid

[0500] Using General Procedure B with 3.17 g (5.3 mmol)(R)-1-[[4-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-2,5-dihydroxy-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 2.2 g (99%) of the title compound as a whitecrystalline solid. MS m/e (%): 421 (M+H⁺, 100).

EXAMPLE 65(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid

[0501] a)(R)-1-[[3-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0502] Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzylester hydrochloride and 800 mg (4.1 mmol) 1,3-phenylenediacetic acidafforded, after flash chromatography (EtOAc), 1.93 g (84%) of the titlecompound as a colorless oil.

[0503] MS m/e (%): 586 (M+NH₄ ⁺, 100), 569 (M+H⁺, 60).

[0504] b)(R)-1-[[3-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid

[0505] Using General Procedure B with 1.84 g (3.2 mmol)(R)-1-[[3-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 1.21 g (97%) of the title compound as a whitefoam. MS m/e (%): 421 (M+H⁺, 100).

EXAMPLE 66(R)-1-[4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid

[0506] a)(R)-1-[4-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0507] Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzylester hydrochloride and 2.0 g (12.0 mmol) benzene-1,4-dioic acidafforded, after flash chromatography (EtOAc), 4.66 g (72%) of the titlecompound as a yellow oil. MS m/e (%): 558 (M+NH₄ ⁺, 100), 541 (M+H⁺,95).

[0508] b)(R)-1-[4-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid

[0509] Using General Procedure B with 4.66 g (8.62 mmol)(R)-1-[4-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 3.05 g (95%) of the title compound as acolorless foam. MS m/e (%): 378 (M+NH₄ ⁺, 100), 361 (M+H⁺, 55).

EXAMPLE 67(R)-1-[3-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid

[0510] a)(R)-1-[3-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0511] Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzylester hydrochloride and 2.0 g (12.0 mmol) benzene-1,3-dioic acidafforded, after flash chromatography (EtOAc), 4.68 g (72%) of the titlecompound as a yellow oil. MS m/e (%): 558 (M+NH₄ ⁺, 100), 541 (M+H⁺,90).

[0512] b)(R)-1-[3-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid

[0513] Using General Procedure B with 2.83 g (5.24 mmol)(R)-1-[3-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-benzoyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 1.9 g (100%) of the title compound as acolorless foam. MS m/e (%): 378 (M+NH₄ ⁺, 100), 361 (M+H⁺, 35).

EXAMPLE 68(R)-1-[6-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid

[0514] a)(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0515] Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzylester hydrochloride and 2.0 g (12.0 mmol) pyridine-2,6-dicarboxylic acidafforded, after flash chromatography (EtOAc), 5.0 g (77%) of the titlecompound as a yellow oil. MS m/e (%): 559 (M+NH₄ ⁺, 60), 542 (M+H⁺,100).

[0516] b)(R)-1-[6-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid

[0517] Using General Procedure B with 3.2 g (5.9 mmol)(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 1.9 g (90%) of the title compound as a whitefoam. MS m/e (%): 379 (M+NH₄ ⁺, 100), 362 (M+H⁺, 65).

EXAMPLE 69(R)-1-[5-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-thiophene-2-carbonyl]-pyrrolidine-2-carboxylicacid

[0518] a)(R)-1-[5-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-thiophene-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0519] Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzylester hydrochloride and 700 mg (4.1 mmol) thiophene-2,5-dicarboxylicacid afforded, after flash chromatography (EtOAc), 1.84 g (84%) of thetitle compound as a yellow crystalline solid. MS m/e (%): 564 (M+NH₄ ⁺,70), 547 (M+H⁺, 100).

[0520] b)(R)-1-[5-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-thiophene-2-carbonyl]-pyrrolidine-2-carboxylicacid

[0521] Using General Procedure B with 1.84 g (3.3 mmol)(R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidine-1-carbonyl]-thiophene-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 770 mg (63%) of the title compoundRO-64-2667/000 as a white crystalline solid. MS m/e (%): 365 ([M−H]⁻,65).

EXAMPLE 70(R)-1-[5-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-furan-2-carbonyl]-pyrrolidine-2-carboxylicacid

[0522] a)(R)-1-[5-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-furan-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0523] Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzylester hydrochloride and 640 mg (4.1 mmol) furan-2,5-dicarboxylic acidafforded, after flash chromatography (EtOAc), 1.7 g (78%) of the titlecompound as a yellow oil. MS m/e

[0524] b)(R)-1-[5-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-furan-2-carbonyl]-pyrrolidine-2-carboxylicacid

[0525] Using General Procedure B with 1.7 g (3.2 mmol)(R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidine-1-carbonyl]-furan-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 1.02 g (91%) of the title compound as a whitefoam. MS m/e (%): 351 (M+H⁺, 100).

EXAMPLE 71(S)-1-[6-[(S)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0526] a)(S)-1-[6-[(S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0527] Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzylester hydrochloride and 300 mg (2.1 mmol) adipic acid afforded, afterflash chromatography (EtOAc), 1.07 g (100%) of the title compound as acolorless oil. MS m/e (%): 521 (M+H⁺, 100).

[0528] b)(S)-1-[6-[(S)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0529] Using General Procedure B with 1.07 g (2.1 mmol)(S)-1-[6-[(S)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 609 mg (87%) of the title compound as a whitecrystalline solid. MS m/e (%): 341 (M+H⁺, 100).

EXAMPLE 72

[0530](S)-1-[[4-[2-[(S)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid

[0531] a)(S)-1-[[4-[2-[(S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0532] Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzylester hydrochloride and 400 mg (2.1 mmol) 1,4-phenylenediacetic acidafforded, after flash chromatography (EtOAc), 1.07 g (91%) of the titlecompound as a colorless oil.

[0533] MS m/e (%): 586 (M+NH₄ ⁺, 100), 569 (M+H⁺, 97).

[0534] b)(S)-1-[[4-[2-[(S)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid

[0535] Using General Procedure B with 1.07 g (1.88 mmol)(S)-1-[[4-[2-[(S)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 410 mg (56%) of the title compound as a whitecrystalline solid. MS m/e (%): 389 (M+H⁺, 100).

EXAMPLE 73(S)-1-[[2-[2-[(S)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0536] a)(S)-1-[[2-[2-[(S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0537] Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzylester hydrochloride and 790 mg (2.1 mmol) 1,2-phenylenedioxyacetic acidafforded, after flash chromatography (EtOAc), 1.08 g (87%) of the titlecompound as a colorless oil.

[0538] MS m/e (%): 601 (M+H⁺, 100).

[0539] b)(S)-1-[[2-[2-[(S)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid

[0540] Using General Procedure B with 1.08 g (1.8 mmol)(S)-1-[[2-[2-[(S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 717 mg (95%) of the title compound as a whitecrystalline solid. MS m/e (%): 421 (M+H⁺, 100).

EXAMPLE 74(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-naphthalen-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0541] a) 2-Diazo-1-(4-diazoacetyl-naphthalen-1-yl)-ethanone

[0542] To a stirred solution of 3.0 g (13.9 mmol)naphthalene-1,4-dicarboxylic acid and 4.4 ml (30.6 mmol) triethylaminein 200 ml THF at -15° C. was added dropwise 2.9 ml (30.6 mmol) ethylchloroformate. After stirring for 15 min, 250 ml (approx. 0.3 M, approx.75 mmol) of an ethereal solution of diazomethane was added at 0° C. andstirring continued for 16 h at room temperature. The reaction mixturewas then washed sequentially with saturated sodium bicarbonate solution,saturated ammonium chloride solution and finally with saturated brine,and the aqueous phases back-extracted with ether. The combined organicextracts were dried over magnesium sulphate and concentrated in vacuo.Flash chromatography (gradient: 15-50% EtOAc/hexane) afforded 450 mg(12%) of the title compound as a yellow crystalline solid. MS m/e (%):323 ([M+OAc]⁻, 100).

[0543] b) (4-Carboxymethyl-naphthalen-1-yl)-acetic acid

[0544] To a stirred solution of 450 mg (1.7 mmol)2-diazo-1-(4-diazoacetyl-naphthalen-1-yl)-ethanone in 20 ml THF at -20°C. were added sequentially in the dark 1.5 ml water, 86 mg (375 mmol)silver benzoate (0.22 equiv.) and 687 ml (4.9 mmol) triethylamine (2.9equiv.) and stirring continued for 2 h at room temperature. The reactionmixture was then diluted with 100 ml ether and extracted twice withsaturated sodium bicarbonate solution. The combined aqueous phases wereextracted three times with ether, then acidified with concentratedhydrochloric acid and extracted a further three times with ether. Thelatter organic extracts were combined and dried over sodium sulphate andconcentrated in vacuo to afford 330 mg (80%) of the title compound as ayellow crystalline solid. MS m/e (%): 244 (M+, 100), 199 (M−CO₂H, 80).

[0545] c)(R)-1-[[4-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-naphthalen-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0546] Using General Procedure A with 200 mg (0.82 mmol) D-Prolinebenzyl ester hydrochloride and 100 mg (0.41 mmol)(4-carboxymethyl-naphthalen-1-yl)-acetic acid afforded, after flashchromatography (EtOAc), 188 mg (75%) of the title compound as acolorless oil. MS m/e (%): 636 (M+NH₄ ⁺, 100), 619 (M+H⁺, 75).

[0547] d)(R)-1-[[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-naphthalen-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0548] Using General Procedure B with 130 mg (0.21 mmol)(R)-1-[[4-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-naphthalen-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 79 mg (86%) of the title compound as a whitecrystalline solid. MS m/e (%): 437 ([M−H]⁻, 100).

EXAMPLE 75(R)-1-[[6-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-pyridin-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0549] a) (6-Cyanomethyl-pyridin-2-yl)-acetonitrile

[0550] To a stirred solution of 3.47 g (13.1 mmol)2,6-bis(bromomethyl)pyridine in 50 ml dichloromethane was added dropwisea solution of 4.1 g (26.2 mmol) tetraethylammonium cyanide in 20 mldichloromethane and the reaction mixture then heated at 45° C. for 72 h.The reaction mixture was then cooled to room temperature and filtered.The filtrate was concentrated in vacuo, resuspended in ethyl acetate,filtered once again, and the second filtrate concentrated in vacuo.Flash chromatography (33% EtOAc/hexane) afforded 1.77 g (84%) of thetitle compound as a white crystalline solid. MS m/e (%): 157 (M⁺, 100),130 ([M−HCN]⁺, 95), 90 (55).

[0551] b) (6-Carboxymethyl-pyridin-2-yl)-acetic acid

[0552] A solution of 3.0 g (19.1 mmol)(6-cyanomethyl-pyridin-2-yl)-acetonitrile in 30 ml concentratedhydrochloric acid was heated at 100° C. for 24 h. The reaction mixturewas then cooled to room temperature and concentrated in vacuo. Theresidue was redissolved in water, activated charcoal added, and themixture heated at 50° C. for 30 min. After removal of the charcoal byfiltration, the filtrate was concentrated in vacuo and the residuerecrystallised from water at 4° C. to afford 2.48 g (100%) of the titlecompound as an off-white crystalline solid. ¹H NMR d (250 MHz, D₂O) 8.42(1H, t, J=8 Hz), 7.80 (2H, d, J=8 Hz).

[0553] c)(R)-1-[[6-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-pyridin-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0554] Using General Procedure A with 9.7 g (40 mmol) D-Proline benzylester hydrochloride and 3.9 g (20 mmol)(6-carboxymethyl-pyridin-2-yl)-acetic acid afforded, after flashchromatography (gradient: 0-10% MeOH/EtOAc), 890 mg (8%) of the titlecompound as a yellow oil. MS m/e (%): 570 (M+H⁺, 100).

[0555] d)(R)-1-[[6-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-pyridin-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0556] Using General Procedure B with 890 mg (1.56 mmol)(R)-1-[[6-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-pyridin-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 410 mg (67%) of the title compound as ayellow crystalline solid. MS m/e (%): 390 (M+H⁺, 100).

EXAMPLE 76(R)-1-[[5-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-thiophen-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0557] a) 2,5-Bis-chloromethyl-thiophene

[0558] To 63.4 ml of a 37% aqueous solution of formaldehyde was addeddropwise with ice-cooling 15.3 ml of concentrated hydrochloric acid andthen 20 ml (0.25 mol) thiophene was added dropwise and stirringcontinued for 90 min at room temperature. The reaction mixture was thenextracted with ether and the organic phases washed sequentially withwater, saturated sodium bicarbonate solution and finally with saturatedbrine. The aqueous phases were back-extracted with ether and thecombined organic extracts were dried over sodium sulphate andconcentrated in vacuo to afford 38.8 g (86%) of the title compoundRO-64-4463/000 as an amber-colored oil. MS m/e (%): 184 (M⁺, 8), 182(M⁺, 15), 180 (M⁺, 24), 147 ([M−Cl]⁺, 44), 145 ([M−Cl]⁺, 100), 110 (64).

[0559] b) (5-Cyanomethyl-thiophen-2-yl)-acetonitrile

[0560] To a stirred solution of 15 g (82.8 mmol)2,5-bis-chloromethyl-thiophene in 500 ml dichloromethane was addeddropwise a solution of 28.5 g (182 mmol) tetraethylammonium cyanide in100 ml dichloromethane and the reaction mixture then heated at 45° C.for 24 h. The reaction mixture was then cooled to room temperature andwashed twice with water. The organic phase was dried over sodiumsulphate and concentrated in vacuo. Flash chromatography (20%EtOAc/hexane) afforded 4.88 g (36%) of the title compound as a yellowoil. MS m/e (%): 162 (M⁺, 44), 122 ([M−CH₂CN]⁺, 100).

[0561] c) (5-Carboxymethyl-thiophen-2-yl)-acetic acid

[0562] To a stirred solution of 1.2 g (7.4 mmol)(5-cyanomethyl-thiophen-2-yl)-acetonitrile in 5 ml ethanol and 5 mlwater was added 1.74 g (31.8 mmol) potassium hydroxide and the reactionmixture heated at 100° C. for 1 h. The reaction mixture was then cooledto room temperature and concentrated in vacuo. The residue was acidifiedwith hydrochloric acid and extracted with three times with ether. Thecombined organic phases were dried over magnesium sulphate andconcentrated in vacuo to afford 1.3 g (88%) of the title compound as abrown crystalline solid. MS m/e (%): 221 ([M+Na−H]⁻, 50), 199 ([M−H]⁻,45), 155 ([M−CO₂H]⁻, 100).

[0563] d)(R)-1-[[5-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-thiophen-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0564] Using General Procedure A with 2.23 g (13 mmol) D-Proline benzylester hydrochloride and 1.3 g (6.5 mmol)(5-carboxymethyl-thiophen-2-yl)-acetic acid afforded, after flashchromatography (gradient: 0-10% MeOH/EtOAc), 2.6 g (79%) of the titlecompound as a yellow oil. MS m/e (%): 524 (M+NH₄ ⁺, 90), 507 (M+H⁺, 10),451 ([M+H−C₄H₈]⁺, 30), 395 ([M+H−2C₄H₈]⁺, 100).

[0565] e)(R)-1-[[5-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-2-oxo-ethyl]-thiophen-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid

[0566] Using General Procedure B with 600 mg (1.18 mmol)(R)-1-[[5-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-thiophen-2-yl]-acetyl]-pyrrolidine-2-carboxylicacid tert-butyl ester afforded 100 mg (21%) of the title compound as abeige crystalline solid. MS m/e (%): 395 (M+H⁺, 100).

EXAMPLE 77(R)-1-[(2R,5S)-6-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0567] a) (3R,6S)-3,6-Dimethoxy-cyclohexene

[0568] Lit., J. Org. Chem., 53:5695 (1988). To a stirred solution of0.70 g (3.1 mmol) palladium acetate, 16.9 g (156 mmol) benzoquinone and0.4 ml (6.2 mmol) methanesulphonic acid in 200 ml methanol at roomtemperature was added via syringe pump over 4 h a solution of 5.95 ml(62 mmol) 1,3-cyclohexadiene in 5 ml methanol, and stirring continuedfor an additional 16 h. The reaction mixture was extracted three timeswith ether and the combined organic extracts washed successively withwater, 2 M sodium hydroxide solution and saturated brine. The organicphases were dried over sodium sulphate and concentrated in vacuo.Kugelrohr distillation (6 mbar, oven temp 120° C.) afforded 5.42 g (61%)of the title compound as a colorless oil. ¹H NMR d (250 MHz, CDCl₃) 5.92(2H, s), 3.70 (2H, t, J=5 Hz), 3.37 (6H, s), 1.90-1.65 (4H, m).

[0569] b) (2R,5S)-2,5-Dimethoxy-hexanedioic acid

[0570] Lit., J. Org. Chem., 53:5688 (1988). To a stirred solution of 5.0g (35.2 mmol) (3R,6S)-3,6-dimethoxy-cyclohexene in 120 ml acetone and120 ml water were added 37.6 g (176 mmol) sodium periodate and 50 mg(0.24 mmol) ruthenium (III) chloride and stirring contained for 16 h atroom temperature. 5 ml isopropanol was added and stirring continued for30 min, then the reaction mixture filtered and the filtrate concentratedin vacuo to half-volume. 5 g sodium bicarbonate was then addedportionwise, and the mixture extracted three times with ethyl acetate.The combined organic phases were washed with saturated brine, dried oversodium sulphate, and concentrated in vacuo to afford 1.0 g (14%) of thetitle compound as an orange oil. MS m/e (%): 205 ([M−H]⁻, 100).

[0571] c)(R)-1-[(2R,5S)-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0572] Using General Procedure A with 1.51 g (6.2 mmol) D-Proline benzylester hydrochloride and 643 mg (3.1 mmol)(2R,5S)-2,5-Dimethoxy-hexanedioic acid afforded, after flashchromatography (gradient: 10-100% EtOAc/hexane then 10% MeOH/EtOAc), 643mg (36%) of the title compound as a yellow oil. MS m/e (%): 581 (M+H⁺,100).

[0573] d)(R)-1-[(2R,5S)-6-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0574] Using General Procedure B with 640 mg (1.10 mmol)(R)-1-[(2R,5S)-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 440 mg (100%) of the title compound as ayellow solid. MS m/e (%): 399 [M−H]⁻, 100).

EXAMPLE 78 (R)-1-[(2S,5S)- or -[(2 R,5R)-6-[(R)-2-Hydroxymethyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0575] a) Acetic acid (1 RS,4RS)-4-acetoxy-cyclohex-2-enyl ester

[0576] Lit., J. Org. Chem., 49:4619 (1984). To a stirred solution of 2.8g (12.5 mmol) palladium acetate, 27.2 g (267 mmol) lithium acetate, and7.64 g (70.7 mmol) benzoquinone in 200 ml acetic acid at roomtemperature were added 26.1 g (300 mmol) manganese dioxide and asolution of 23.8 ml (250 mmol) 1,3-cyclohexadiene in 400 ml pentane, andstirring continued for 16 h. The two-phase reaction mixture wasseparated and the acetic acid phase extracted twice with pentane. Thecombined organic extracts were washed successively with saturated brine,water, and 2 M sodium hydroxide solution, then the organic phases weredried over sodium sulphate and concentrated in vacuo. Recrystallisationfrom pentane afforded 16.1 g (33%) of the title compound as an off-whitecrystalline solid. MS m/e (%): 138 ([M−AcOH]⁺, 8), 96 ([MAcOH—COCH₂]⁺,100), 43 (40).

[0577] b) (1 RS,4RS)-Cyclohex-2-ene-1,4-diol

[0578] Lit., J. Org. Chem., 49:4619 (1984). To a stirred solution of19.8 g (99.8 mmol) acetic acid (1 RS,4RS)-4-acetoxy-cyclohex-2-enylester in 500 ml methanol was added 120 ml 2 M sodium hydroxide solutionand the reaction mixture refluxed for 15 min. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo to 100 ml,and then saturated with sodium hydroxide pellets. The mixture wasextracted repeatedly with ethyl acetate and the combined organic phasesdried over sodium sulphate and concentrated in vacuo to afford 10.2 g(90%) of the title compound as an of-white crystalline solid. MS m/e(%): 113 ([M−H]+, 13), 96 ([M−H₂O]⁺, 36), 70 ([M−H₂C═CHOH]⁺, 100).

[0579] c) (3RS,6RS)-3,6-Dimethoxy-cyclohexene

[0580] Lit., J. Org. Chem., 53:5695 (1988). To 14.3 g (328 mmol) sodiumhydride (55% dispersion in oil) was added dropwise at 0° C. withstirring a solution of 10.1 g (88.5 mmol)(1RS,4RS)-cyclohex-2-ene-1,4-diol in 100 ml THF. 34 ml (546 mmol) methyliodide was then added and stirring continued for an additional 48 h atroom temperature. The reaction was quenched with saturated ammoniumchloride solution and extracted with ether. The combined organicextracts were washed successively with saturated ammonium chloridesolution and saturated brine, dried over sodium sulphate, andconcentrated in vacuo to afford 11.5 g (91%) of the title compound as ayellow oil. ¹H NMR d (250 MHz, CDCl₃) 5.90 (2H, s), 3.82 (2H, br t),3.37 (6H, s), 2.10 (2H, m), 1.51 (2H, m).

[0581] d) (2RS,5RS)-2,5-Dimethoxy-hexanedioic acid

[0582] To a stirred solution of 6.0 9 (42.2 mmol)(3RS,6RS)-3,6-dimethoxy-cyclohexene in 140 ml acetone and 140 ml waterwere added 50.5 g (236 mmol) sodium periodate and 67 mg (0.32 mmol)ruthenium (III) chloride and stirring continued for 16 h at roomtemperature. 10 ml isopropanol was added and stirring continued for 30min, then the reaction mixture filtered and the filtrate concentrated invacuo to half-volume. 5 g sodium bicarbonate was then added portionwise,and the mixture extracted three times with ether. The aqueous phase wasacidified with 25% hydrochloric acid and extracted repeatedly with ethylacetate. The combined organic phases were dried over sodium sulphate,and concentrated in vacuo to afford 1.32 g (15%) of the title compoundRO-64-5650/000 as an orange oil. Continuous extraction of the aqueousphase over 48 h afforded another 608 mg (7%) of product. MS m/e (%): 161([M−CO₂H]⁺, 20), 113 (58),. 101 (69), 85 (50), 71 (100).

[0583] e) (R)-1-[(2S,5S)- or-[(2R,5R)-6-[(R)-2-Benzyloxymethyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl and (R)-1-[(2R,5R)- or[(2S,5S)-6-[(R)-2-Benzyloxymethyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl

[0584] Using General Procedure A with 1.67 g (6.9 mmol) D-Proline benzylester hydrochloride and 250 mg (1.2 mmol)(2RS,5RS)-2,5-dimethoxy-hexanedioic acid afforded, after flashchromatography (gradient: 50-100% EtOAc/hexane then 10% MeOH/EtOAc), 95mg (13%) of the title compound (mixture of 2 diastereomers) as a brownoil, and 172 mg (24%) of the title compound (single separateddiastereomer) as a yellow oil. MS m/e (%): 581 (M+H⁺, 100).

[0585] f) (R)-1-[(2S,5S)- or -[(2R,5R)-6-[(R)-2-Hydroxymethyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0586] Using General Procedure B with 160 mg (0.28 mmol) (R)-1-[(2R,5R)-or[(2S,5S)-6-[(R)-2-benzyloxymethyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl afforded 90 mg (82%) of the title compound as a white foam.MS m/e (%): 399 ([M−H]⁻, 100), 355 ([M−H—CO₂]⁻, 61).

EXAMPLE 79 (R)-1-[(2R,5R)- or-[(2S,5S)-6-[(R)-2-Hydroxymethyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0587] Using General Procedure B with 95 mg (0.28 mmol) (R)-1-[(2S,5S)-or-[(2R,5R)-6-[(R)-2-benzyloxymethyl-pyrrolidin-1-yl]-2,5-dimethoxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl afforded 70 mg (100%) of the title compound as a white foam.

[0588] MS m/e (%): 399 ([M−H]⁻, 100), 355 ([M−H—CO₂]⁻, 20).

EXAMPLE 80(R)-1-[2,5-Dibenzyl-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0589] a) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-dibenzyl-hex-3-enedioic acid diethyl ester

[0590] To a stirred solution of 688 mg (3.44 mmol)trans-2-butene-1,4-dicarboxylic acid diethyl ester in 35 ml THF wasadded 1.46 g (34.4 mmol) anhydrous lithium chloride and the resultingsuspension cooled to −78° C. 3.44 ml (6.88 mmol) of a 2 M solution ofLDA in THF was added dropwise and stirring continued for 45 min. 0.82 ml(6.9 mmol) benzyl bromide was then added and stirring continued for 1 hat −78° C. and 10 min at 0° C. The reaction was quenched at thistemperature by addition of saturated ammonium chloride solution and themixture extracted three times with ether. The combined organic phaseswere washed with saturated brine, dried over sodium sulphate, andconcentrated in vacuo. Flash chromatography (5% EtOAc in hexane)afforded 927 mg (71%) of the title compound as a yellow oil. MS m/e (%):398 ([M+NH₄]⁺, 100).

[0591] b) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-dibenzyl-hex-3-enedioic

[0592] To a stirred solution of 200 mg (0.53 mmol) mixture of(E)-(2R,5S)- and -(2RS,5SR)-2,5-dibenzyl-hex-3-enedioic acid diethylester in 5 ml THF was added 4.3 ml (4.3 mmol) of 1 M sodium hydroxidesolution. After stirring for 68 h at room temperature, the reactionmixture was acidified to pH 3 by addition of 1 M hydrochloric acid andextracted three times with ethyl acetate. The combined organic phaseswere washed successively with water and with saturated brine, dried oversodium sulphate, and concentrated in vacuo. Flash chromatography (50%EtOAc in hexane containing 1% AcOH) afforded 127 mg (74%) of the titlecompound as a white crystalline solid. MS m/e (%): 342 ([M+NH₄]⁺, 100).

[0593] c)(E)-(R)-1-[2,5-Dibenzyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers)

[0594] Using General Procedure A with 1.04 g (4.30 mmol) D-Prolinebenzyl ester hydrochloride and 700 mg (2.16 mmol) mixture of(E)-(2R,5S)- and -(2RS,5SR)-2,5-dibenzyl-hex-3-enedioic acid diethylester afforded, after flash chromatography (5% MeOH in EtOAc), 926 mg(61%) of the title compound as a yellow oil. MS m/e (%): 716 (M+NH₄ ⁺,100), 699 (M+H⁺, 85).

[0595] d)(R)-1-[2,5-Dibenzyl-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0596] Using General Procedure B with 926 mg (1.33 mmol)(E)-(R)-1-[2,5-dibenzyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers) afforded 610 mg (89%) ofthe title compound as a white crystalline solid. MS m/e (%): 519([M−H]⁻, 100).

EXAMPLE 81(R)-1-[2,5-Dibutyl-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (1 out of 3 possible diastereomers)

[0597] a) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-dibutyl-hex-3-enedioic acid diethyl ester

[0598] To a stirred solution of 2.0 g (9.99 mmol)trans-2-butene-1,4-dicarboxylic acid diethyl ester in 80 ml THF wasadded 2.54 g (59.9 mmol) anhydrous lithium chloride and the resultingsuspension cooled to −78° C. 10.0 ml (20.0 mmol) of a 2 M solution ofLDA in THF was added dropwise and stirring continued for 45 min. 2.2 ml(20.4 mmol) butyl bromide was then added and stirring continued for 15min at −78° C., then 30 min at 0° C., and then 4 h at room temperature.The reaction was quenched by addition of saturated ammonium chloridesolution and the mixture extracted three times with ether. The combinedorganic phases were washed successively with saturated ammonium chloridesolution, water, and saturated brine, dried over sodium sulphate, andconcentrated in vacuo. Successive flash chromatography (10% EtOAc inhexane for first column; then gradient: 10-100% toluene in cyclohexanefor second column) afforded 509 mg (16%) of the title compound as ayellow oil. MS m/e (%): 330 ([M+NH₄]⁺, 100).

[0599] b) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-dibutyl-hex-3-enedioic acid

[0600] To a stirred solution of 435 mg (1.39 mmol) mixture of(E)-(2R,5S)- and -(2RS,5SR)-2,5-dibutyl-hex-3-enedioic acid diethylester in 10 ml THF was added 26 ml (26 mmol) of 1 M sodium hydroxidesolution. After stirring for 72 h at room temperature, the reactionmixture was acidified to pH 3 by addition of 1 M hydrochloric acid andextracted three times with ethyl acetate. The combined organic phaseswere washed successively with water and with saturated brine, dried oversodium sulphate, and concentrated in vacuo to afford 346 mg (97%) of thetitle compound as a white crystalline solid. MS m/e (%): 255 ([M−H]⁻,60), 211 ([M−H—CO₂]⁻, 100).

[0601] c) (E)-(R)-1-[2,5-Dibutyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 2 out of 3 possible diastereomers) and(E)-(R)-1-[2,5-Dibutyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (principally 1 out of 3 possible diastereomers)

[0602] Using General Procedure A with 653 mg (2.70 mmol) D-Prolinebenzyl ester hydrochloride and 346 mg (1.35 mmol) mixture of(E)-(2R,5S)- and -(2RS,5SR)-2,5-dibutyl-hex-3-enedioic acid afforded,after flash chromatography (gradient: 33-50% EtOAc in hexane), 148 mg(17%) of the title compound RO-64-3271/000 (mixture of 2 diastereomers)as a yellow oil and 116 mg (14%) of the title compound (singlediastereomer) as a yellow oil. MS m/e (%): 648 (M+NH₄ ⁺, 90), 631 (M+H⁺,100).

[0603] d) (R)-1-[2,5-Dibutyl-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (1 out of 3 possible diastereomers)

[0604] Using General Procedure B with 140 mg (0.22 mmol)(E)-(R)-1-[2,5-dibutyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (principally 1 out of 3 possible diastereomers)afforded 81 mg (81%) of the title compound RO-64-3273/000 (singlediastereomer) as a colorless oil.

[0605] MS m/e (%): 451 ([M−H]⁻, 100).

EXAMPLE 82 (R)-1-[2,5-Dibutyl-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (mixture of 2 out of 3 possible diastereomers)

[0606] Using General Procedure B with 110 mg (0.22 mmol)(E)-(R)-1-[2,5-dibutyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 2 out of 3 possible diastereomers)afforded 69 mg (88%) of the title compound (2 diastereomers) as acolorless oil. MS m/e (%): 451 ([M−H]⁻, 100).

EXAMPLE 83(R)-1-[2,5-Diisopropyl-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0607] a) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-diisopropyl-hex-3-enedioic acid diethyl ester

[0608] To a stirred solution of 5.0 g (25.0 mmol)trans-2-butene-1,4-dicarboxylic acid diethyl ester in 120 ml THf wasadded 6.35 g (150 mmol) anhydrous lithium chloride and the resultingsuspension cooled to −78° C. 25.0 ml (50.0 mmol) of a 2 M solution ofLDA in THF was added dropwise and stirring continued for 45 min. 4.7 ml(50 mmol) isopropyl bromide was then added and stirring continued for 15min at −78° C., then 4 h at 0° C., and then 48 h at room temperature.The reaction was quenched by addition of saturated ammonium chloridesolution and the mixture extracted three times with ether. The combinedorganic phases were washed successively with saturated ammonium chloridesolution, water, and saturated brine, dried over sodium sulphate, andconcentrated in vacuo. Successive flash chromatography (20% EtOAc inhexane for first column; 5% EtOAc in hexane for second column; 10% EtOAcin hexane for third column) afforded 259 mg (4%) of the title compoundas a yellow oil. MS m/e (%): 302 ([M+NH₄]⁺, 100).

[0609] b) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-diisopropyl-hex-3-enedioic

[0610] To a stirred solution of 108 mg (0.38 mmol) mixture of(E)-(2R,5S)- and -(2RS,5SR)-2,5-diisopropyl-hex-3-enedioic acid diethylester in 5 ml THF was added 10 ml (10 mmol) of 1 M sodium hydroxidesolution. After stirring for 96 h at room temperature, the reactionmixture was acidified to pH 3 by addition of 1 M hydrochloric acid andextracted three times with ethyl acetate. The combined organic phaseswere washed successively with water and with saturated brine, dried oversodium sulphate, and concentrated in vacuo to afford 70 mg (81%) of thetitle compound as a yellow oil. MS m/e (%): 227 ([M−H]⁻, 100).

[0611] c)(E)-(R)-1-[2,5-Diisopropyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of the 3 diastereomers)

[0612] Using General Procedure A with 114 mg (0.47 mmol) D-Prolinebenzyl ester hydrochloride and 54 mg (0.24 mmol) mixture of (E)-(2R,5S)-and -(2RS,5SR)-2,5-diisopropyl-hex-3-enedioic afforded, after flashchromatography (gradient: 33-50% EtOAc in hexane), 15 mg (11%) of thetitle compound as a colorless oil. MS m/e (%): 620 (M+NH₄ ⁺, 100).

[0613] d)(R)-1-[2,5-Diisopropyl-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0614] Using General Procedure B with 41 mg (0.07 mmol)(E)-(R)-1-[2,5-diisopropyl-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of the 3 diastereomers) afforded 28 mg (100%)of the title compound as a colorless oil. MS m/e (%):423 ([M−H]⁻, 100).

EXAMPLE 84(R)-1-[5-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-7-methoxy-2-(2-methoxy-ethyl)-heptanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers

[0615] a) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-bis-(2-methoxy-ethyl)-hex-3-enedioic acid diethyl ester

[0616] To a stirred solution of 5.0 g (25.0 mmol)trans-2-butene-1,4-dicarboxylic acid diethyl ester in 125 ml THF wasadded 6.35 g (150 mmol) anhydrous lithium chloride and the resultingsuspension cooled to −78° C. 25.0 ml (50.0 mmol) of a 2 M solution ofLDA in THF was added dropwise and stirring continued for 45 min. 7.4 ml(78.7 mmol) 2-methoxyethyl bromide was then added and stirring continuedfor 15 min at −78° C., then 1 h at 0° C., and then 2 h at roomtemperature. The reaction was quenched by addition of saturated ammoniumchloride solution and the mixture extracted three times with ether. Thecombined organic phases were washed successively with saturated ammoniumchloride solution, water, and saturated brine, dried over sodiumsulphate, and concentrated in vacuo. Flash chromatography (50% toluenein EtOAc) afforded 1.29 g (16%) of the title compound as a yellow oil.

[0617] MS m/e (%): 334 ([M+NH₄]⁺, 100).

[0618] b) Mixture of (E)-(2R,5S)- and-(2RS,5SR)-2,5-bis-(2-methoxy-ethyl)-hex-3-enedioic acid

[0619] To a stirred solution of 1.29 g (4.08 mmol) mixture of(E)-(2R,5S)- and -(2RS,5SR)-2,5-bis-(2-methoxy-ethyl)-hex-3-enedioicacid diethyl ester in 10 ml THF was added 33 ml (33 mmol) of 1 M sodiumhydroxide solution. After stirring for 18 h at room temperature, thereaction mixture was acidified to pH 3 by addition of 1 M hydrochloricacid and extracted three times with ethyl acetate. The combined organicphases were washed successively with water and with saturated brine,dried over sodium sulphate, and concentrated in vacuo to afford 894 mg(84%) of the title compound as a yellow oil. MS m/e (%): 259 ([M−H]⁻,100).

[0620] c)(E)-(R)-1-[5-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-7-methoxy-2-(2-methoxy-ethyl)-heptanoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers)

[0621] Using General Procedure A with 1.86 g (7.69 mmol) D-Prolinebenzyl ester hydrochloride and 894 mg (3.84 mmol) mixture of(E)-(2R,5S)- and -(2RS,5SR)-2,5-bis-(2-methoxy-ethyl)-hex-3-enedioicacid afforded, after successive flash chromatography (gradient 50%-100%EtOAc in hexane then 10% MeOH in EtOAc for first column; 20% toluene inEtOAc for second column; 20% toluene in EtOAc for third column;gradient: 25-20% toluene in EtOAc for fourth column), 146 mg (7%) of thetitle compound as a light yellow oil. MS m/e (%): 652 (M+NH₄ ⁺, 50), 635(M+H⁺, 100).

[0622] d)(R)-1-[5-[(R)-2-Carboxy-pyrrolidine-1-carbonyl]-7-methoxy-2-(2-methoxy-ethyl)-heptanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers

[0623] Using General Procedure B with 146 mg (0.23 mmol)(E)-(R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidine-1-carbonyl]-7-methoxy-2-(2-methoxy-ethyl)-heptanoyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of 3 diastereomers) afforded 92 mg (88%) ofthe title compound as a colorless oil. MS m/e (%): 455 ([M−H]⁻, 100).

EXAMPLE 85(R)-1-[2-[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl]-phenyl]-propionyl]-pyrrolidine-2-carboxylicacid (mixture of the 3 diastereomers)

[0624] a) (4-Benzyloxycarbonylmethyl-phenyl)-acetic acid benzyl ester

[0625] To a suspension of 10.0 g (51.5 mmol) benzene-1,4-diacetic acid,0.94 g (7.73 mmol) 4-dimethylaminopyridine and 5.33 ml (51.5 mmol)benzyl alcohol in 150 ml dichloromethane at 0° C. was added 11.85 g(61.8 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and stirringcontinued at 0° C. for 2 h and then at room temperature for 16 h. Thereaction mixture was then washed sequentially with 1 M hydrochloricacid, saturated sodium bicarbonate solution and finally with saturatedbrine, and the aqueous phases back-extracted with dichloromethane. Thecombined organic extracts were dried over sodium sulphate andconcentrated in vacuo. Flash chromatography (50% EtOAc in hexane) thenafforded the title compound as a light yellow oil which crystallised onstanding. MS m/e (%): 374 (M⁺, 10), 283 ([M−Bn]⁺, 16), 239 ([M−Bn—CO2]⁺,18), 91 (Bn⁺, 100).

[0626] b) Mixture of (R)-2-[4-[(S)- and(RS)-2-[4-[(RS)-1-benzyloxycarbonyl-ethyl]-phenyl]-propionic acid benzylester

[0627] To a stirred solution of 2.0 g (5.3 mmol)(4-benzyloxycarbonylmethyl-phenyl)-acetic acid benzyl ester in 80 ml THFwas added 1.35 g (32 mmol) anhydrous lithium chloride and the resultingsuspension cooled to −78° C. 10.7 ml (21.4 mmol) of a 2 M solution ofLDA in THF was added dropwise and stirring continued for 45 min. 1.33 ml(21.3 mmol) methyl iodide was then added and stirring continued for 15min at −78° C., then 20 min at 0° C. The reaction was quenched at thistemperature by addition of saturated ammonium chloride solution and themixture extracted three times with ether. The combined organic phaseswere dried over sodium sulphate, and concentrated in vacuo. Flashchromatography (EtOAc) afforded 2.1 g (100%) of the title compound as abrown oil. MS m/e (%): 420 ([M+NH₄]⁺, 100).

[0628] c) Mixture of (R)-2-[4-[(S)- and(RS)-2-[4-[(RS)-1-carboxy-ethyl)-phenyl]-propionic acid

[0629] A solution of 230 mg (0.57 mmol) mixture of (R)-2-[4-[(S)- and(RS)-2-[4-[(RS)-1-benzyloxycarbonyl-ethyl]-phenyl]-propionic acid benzylester in 20 ml ethanol was stirred with 5 wt % of 10% palladium oncharcoal under 1 atm of hydrogen for 16 h at room temperature. Afterfiltration to remove the catalyst, the reaction mixture was concentratedin vacuo to afford 70 mg (55%) of the title compound as a whitecrystalline solid. MS m/e (%): 222 (M⁺, 23), 177 ([M−CO₂H]⁻, 100), 131.

[0630] d)(R)-1-[2-[4-[2-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl]-phenyl]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of the 3 diastereomers)

[0631] Using General Procedure A with 370 mg (1.53 mmol) D-Prolinebenzyl ester hydrochloride and 170 mg (0.77 mmol) mixture of(R)-2-[4-[(S)- and (RS)-2-[4-[(RS)-1-carboxy-ethyl)-phenyl]-propionicacid afforded, after flash chromatography (EtOAc), 170 mg (38%) of thetitle compound as a colorless oil. MS m/e (%): 614 (M+NH₄ ⁺, 100), 597(M+H⁺, 60).

[0632] e)(R)-1-[2-[4-[2-[(R)-2-Carboxy-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl]-phenyl]-propionyl]-pyrrolidine-2-carboxylicacid (mixture of the 3 diastereomers)

[0633] Using General Procedure B with 170 mg (0.29 mmol)(R)-1-[2-[4-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl]-phenyl]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester (mixture of the 3 diastereomers) afforded 50 mg (42%)of the title compound as a white foam. MS m/e (%): 415 ([M−H]⁻, 100)

EXAMPLE 86(2E,4E)-(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylicacid

[0634] a)(2E,4E)-(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0635] To a stirred suspension of 0.91 g (5.32 mmol)2,5-dimethyl-hex-2,4-dien-1,6-dioic acid in 80 ml dichloromethanecontaining two drops of pyridine was added dropwise at room temperature0.77 ml (10.6 mmol) thionyl chloride and the reaction mixture was thenheated at 50° C. for 2 h. The resulting solution was cooled to 0° C. andadded dropwise to a solution of 2.57 g (10.6 mmol) D-Proline benzylester hydrochloride and 3.0 ml (21.5 mmol) triethylamine in 50 mldichloromethane at 0° C. Stirring was continued for 2 h at 0° C. andthen 24 h at room temperature. The reaction mixture was then washedsequentially with 1 M hydrochloric acid and with water, and the aqueousphases back-extracted with dichloromethane. The combined organicextracts were dried over sodium sulphate and concentrated in vacuo.Flash chromatography (EtOAc) afforded 2.79 g (96%) of the title compoundas a colorless oil. MS m/e (%): 562 (M+NH₄ ⁺, 100), 545 (M+H⁺, 5.

[0636] b) (2E,4E)-(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylicacid

[0637] Using General Procedure B with 1.14 g (2.09 mmol)(2E,4E)-(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylicacid benzyl ester and with dioxane as solvent afforded 127 mg (16%) ofthe title compound as a white solid. MS m/e (%): 365 (M+H⁺, 100).

EXAMPLE 87(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl)-2,5-dimethyl-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid (mixture of 3 diastereomers)

[0638] A solution of 593 mg (1.09 mmol)(2E,4E)-(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylicacid benzyl ester in 15 ml dioxane was stirred with 25 mg (0.11 mmol)platinum (IV) oxide under 1 atm of hydrogen for 72 h at roomtemperature. After filtration to remove the catalyst, the reactionmixture was concentrated in vacuo and azeotroped three times withchloroform on a rotary evaporator to remove last traces of dioxane, thentriturated in ether to afford 400 mg (100%) of the title compound as awhite foam. MS m/e (%): 369 (M+H⁺, 100).

EXAMPLE 88 Mixture of (R)-1-[(3R,4R)- and-[(3S,4S)-3,4-dihydroxy-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0639] a)(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidine-1-carbonyl]-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0640] Using General Procedure A with 5.0 g (20.6 mmol) D-Proline benzylester hydrochloride and 1.5 g (10.3 mmol) trans-3-hexenedioic acidafforded, after flash chromatography (EtOAc), 3.15 g (59%) of the titlecompound as a light yellow oil.

[0641] MS m/e (%): 536 (M+NH₄ ⁺, 100), 519 (M+H⁺, 80).

[0642] b) Mixture of (R)-1-[(3R,4R)- and-[(3S,4S)-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3,4-dihydroxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0643] To a stirred solution of 3.13 g (6.04 mmol)(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidine-1-carbonyl]-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicacid benzyl ester in 10 ml acetone and 10 ml water were added 980 mg(7.25 mmol) 4-methylmorpholine-4-oxide and 0.6 ml of a 2.5% solution ofosmium tetroxide in tert-butanol and stirring continued for 72 h at roomtemperature. 50 ml of 38% sodium hydrogensulphite solution was thenadded at 0° C. and stirring continued for a further 15 min. The reactionmixture was then filtered and extracted three times with ethyl acetate.The combined organic extracts were washed sequentially with 1 Mhydrochloric acid and saturated brine, dried over sodium sulphate, andconcentrated in vacuo to afford 3.34 g (100%) of the title compound as acolorless oil. MS m/e (%): 575 (M+Na⁺, 35), 570 (M+NH₄ ⁺, 55), 553(M+H⁺, 100).

[0644] c) Mixture of (R)-1-[(3R,4R)- and-[(3S,4S)-3,4-dihydroxy-6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0645] Using General Procedure B with 506 mg (0.92 mmol) mixture of(R)-1-[(3R,4R)- and -[(3S,4S)-6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3,4-dihydroxy-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid benzyl ester afforded 341 mg (100%) of the title compound as awhite solid. MS m/e (%): 395 (M+NH₄ ⁺, 55), 373 (M+H⁺, 100).

EXAMPLE 89(E)-(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl)-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid

[0646] a)(E)-(R)-1-[6-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl)-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0647] Using General Procedure A with 1.5 g (8.76 mmol) D-Prolinetert-butyl ester and 630 mg (4.37 mmol) trans-3-hexenedioic acidafforded, after flash chromatography (10% EtOH in EtOAc), 1.59 g (77%)of the title compound as a white crystalline solid. MS m/e (%): 568(M+NH₄ ⁺, 35), 451 (M+H⁺, 100), 395 ([M+H—C₃H₈]⁺, 32), 339 (M+H—2C₃H₈]⁺,40).

[0648] b)(E)-(R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl)-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid

[0649] To a stirred solution of 600 mg (1.33 mmol)(E)-(R)-1-[6-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 15 ml dichloromethane at 0° C. was addeddropwise 4.4 ml (57.8 mmol) trifluoroacetic acid and stirring continuedfor 16 h at room temperature. Concentration in vacuo and azeotropingthree times with chloroform on a rotary evaporator afforded 402 mg (90%)of the title compound as a white foam. MS m/e (%): 339 (M+H⁺, 100).

EXAMPLE 90(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid

[0650] a) (R)-1-Acryloyl-pyrrolidine-2-carboxylic acid benzyl ester

[0651] To a stirred solution of 390 mg (1.6 mmol) D-Proline benzyl esterhydrochloride and 0.47 ml (3.4 mmol) triethylamine in 20 mldichloromethane at 0° C. was added dropwise 0.2 ml (2.4 mmol) acryloylchloride and stirring continued for 24 h at room temperature. Thereaction mixture was then washed sequentially with water, 1 Mhydrochloric acid and once more with water, and the aqueous phasesback-extracted with dichloromethane. The combined organic extracts weredried over sodium sulphate and concentrated in vacuo to afford 420 mg(100%) of the title compound as a colorless oil. MS m/e (%): 259 (M⁺,25), 124 (100), 91 (25), 70 (21).

[0652] b)(R)-1-[3-[[3-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0653] A solution of 400 mg (1.5 mmol)(R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester and 63 ml(0.75 mmol) propylamine in 5 ml acetonitrile was stirred for 16 h atroom temperature, then for 6 h at 45° C., and finally for 16 h at 80° C.Concentration in vacuo and flash chromatography (20% H₂O in acetone)afforded 84 mg (19%) of the title compound as a pale yellow oil. MS m/e(%): 578 (M+H⁺, 100).

[0654] c)(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid

[0655] A solution of 84 mg (0.15 mmol)(R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester in 3 ml ethanol was stirred with 10 mg 10% palladiumon charcoal under 1 atm of hydrogen for 16 h at room temperature. Afterfiltration to remove the catalyst, concentration in vacuo afforded 58 mg(100%) of the title compound as a white solid. MS m/e (%): 398 (M+H⁺,100).

EXAMPLE 91(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-cyclopropylmethyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid

[0656] a)(R)-1-[3-[[3-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-cyclopropylmethyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester

[0657] A solution of 444 mg (1.71 mmol)(R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester and 74 ml(0.85 mmol) cyclopropylmethylamine in 5 ml acetonitrile was stirred for1 h at room temperature, then for 16 h at 80° C. Concentration in vacuoand flash chromatography (gradient: 0-100% MeOH in EtOAc) afforded 220mg (44%) of the title compound as a yellow oil. MS m/e (%): 590 (M+H⁺,100).

[0658] b)(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-cyclopropylmethyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid

[0659] A solution of 220 mg (0.37 mmol)(R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-cyclopropylmethyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid benzyl ester in 20 ml isopropanol was stirred with 10 mg 10%palladium on charcoal under 1 atm of hydrogen for 16 h at roomtemperature. After filtration to remove the catalyst, concentration invacuo afforded 153 mg (100%) of the title compound as a yellow solid. MSm/e (%): 408 ([M−H]⁻, 100).

EXAMPLE 92(R)-1-[3-[(3,4-Dimethoxy-benzyl)-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0660] a) (R)-1-Acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester

[0661] To a stirred solution of 5.0 g (29.2 mmol) D-Proline tert-butylester and 4.5 ml (32.1 mmol) triethylamine in 180 ml dichloromethane at0° C. was added dropwise 3.6 ml (43.8 mmol) acryloyl chloride andstirring continued for 48 h at room temperature. The reaction mixturewas then washed sequentially with water, saturated ammonium chloridesolution, once more with water and then with saturated brine, and theaqueous phases back-extracted with dichloromethane. The combined organicextracts were dried over sodium sulphate and concentrated in vacuo toafford 6.6 g (100%) of the title compound as a yellow oil. MS m/e (%):243 (M+NH₄ ⁺, 33), 226 (M+H⁺, 100).

[0662] b)(R)-1-[3-[[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(3,4-dimethoxy-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0663] A solution of 1.0 g (4.44 mmol)(R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.33ml (2.22 mmol) veratrylamine in 25 ml acetonitrile was stirred for 16 hat 80° C. Concentration in vacuo and flash chromatography (gradient:0-10% MeOH in EtOAc) afforded 150 mg (10%) of the title compound as alight brown oil.

[0664] MS m/e (%): 618 (M+H⁺, 100).

[0665] c)(R)-1-[3-[(3,4-Dimethoxy-benzyl)-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0666] To a stirred solution of 150 mg (0.24 mmol)(R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(3,4-dimethoxy-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane at 0° C. was addeddropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h atroom temperature. Concentration in vacuo and azeotroping three timeswith chloroform on a rotary evaporator afforded, after trituration inether, 130 mg (87%) of the title compound as a yellow crystalline solid.MS m/e (%): 506 (M+H⁺, 100).

EXAMPLE 93(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-(2-methoxy-ethyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0667] a)(R)-1-[3-[[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(2-methoxy-ethyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0668] A solution of 1.0 g (4.44 mmol)(R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.19ml (2.22 mmol) 2-methoxyethylamine in 25 ml acetonitrile was stirred for16 h at 80° C. Concentration in vacuo and flash chromatography(gradient: 0-10% MeOH in EtOAc) afforded 300 mg (23%) of the titlecompound as a light brown oil. MS m/e (%): 526 (M+H⁺, 100).

[0669] b)(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-(2-methoxy-ethyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0670] To a stirred solution of 150 mg (0.29 mmol)(R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(2-methoxy-ethyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane at 0° C. was addeddropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h atroom temperature. Concentration in vacuo and azeotroping three timeswith chloroform on a rotary evaporator afforded, after resuspension inwater and subsequent lyophilisation, 100 mg (67%) of the title compoundas a yellow oil. MS m/e (%): 436 (M+Na⁺, 35), 414 (M+H⁺, 100).

EXAMPLE 94(R)-1-[3-[Benzyl-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0671] a)(R)-1-[3-[Benzyl-[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0672] A solution of 1.0 g (4.44 mmol)(R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.24ml (2.22 mmol) benzylamine in 25 ml acetonitrile was stirred for 16 h at80° C. Concentration in vacuo and flash chromatography (gradient: 0-10%MeOH in EtOAc) afforded 470 mg (34%) of the title compound as a yellowoil. MS m/e (%): 558 (M+H⁺, 100).

[0673] b)(R)-1-[3-[Benzyl-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0674] To a stirred solution of 200 mg (0.36 mmol)(R)-1-[3-[benzyl-[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane at 0° C. was addeddropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h atroom temperature. Concentration in vacuo and azeotroping three timeswith chloroform on a rotary evaporator afforded, after trituration inether, 160 mg (80%) of the title compound as a yellow crystalline solid.MS m/e (%): 468 (M+Na⁺, 30), 446 (M+H⁺, 100).

EXAMPLE 95(R)-1-[3-[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0675] a)(R)-1-[3-[[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(4-trifluoromethyl-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0676] A solution of 1.0 g (4.44 mmol)(R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.32ml (2.22 mmol) para-trifluoromethylbenzylamine in 25 ml acetonitrile wasstirred for 16 h at 80° C. Concentration in vacuo and flashchromatography (gradient: 0-10% MeOH in EtOAc) afforded 480 mg (31%) ofthe title compound as a light brown oil. MS m/e (%): 626 (M+H⁺, 100).

[0677] b)(R)-1-[3-[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester and(R)-1-[3-[[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-ethyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester

[0678] A solution of 290 mg (0.46 mmol)(R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(4-trifuoromethyl-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 50 ml ethanol was stirred with 30 mg 10%palladium on charcoal under 1 atm of hydrogen for 72 h at roomtemperature. After filtration to remove the catalyst, concentration invacuo and flash chromatography (gradient: 0-100% MeOH in EtOAccontaining 1% Et₃N) afforded 36 mg (17%) of the title compound(R)-1-[3-[3-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester as a yellow oil. MS m/e (%): 468 (M+H⁺, 100).Further flash chromatography of the less polar fractions (gradient:0-20% MeOH in EtOAc containing 1% Et₃N) afforded 87 mg (38%) of theby-product(R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-ethyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester as a yellow oil. MS m/e (%): 496 (M+H⁺, 100).

[0679] c)(R)-1-[3-[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0680] To a stirred solution of 33 mg (0.07 mmol)(R)-1-[3-[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane at 0° C. was addeddropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h atroom temperature. Concentration in vacuo and azeotroping three timeswith chloroform on a rotary evaporator afforded, after resuspension inwater and subsequent lyophilization, 19 mg (76%) of the title compoundas a yellow glassy solid. MS m/e (%): 354 ([M−H]⁻, 100).

EXAMPLE 96(R)-1-[3-[Ethyl-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0681] To a stirred solution of 85 mg (0.17 mmol)(R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-ethyl-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane at 0° C. was addeddropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h atroom temperature. Concentration in vacuo and azeotroping three timeswith chloroform on a rotary evaporator afforded, after resuspension inwater and lyophilization, 63 mg (97%) of the title compound as a yellowcrystalline solid. MS m/e (%): 442 ([M+OAc]⁻, 35), 382 ([M−H]⁻, 100).

EXAMPLE 97(R)-1-[3-[[3-[(R)-2-Carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-(4-trifluoromethyl-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid trifluoroacetate (1:1)

[0682] To a stirred solution of 200 mg (0.32 mmol)(R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(4-trifluoromethyl-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane at 0° C. was addeddropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h atroom temperature. Concentration in vacuo and azeotroping three timeswith chloroform on a rotary evaporator afforded, after trituration inether, 150 mg (75%) of the title compound as a yellow crystalline solid.MS m/e (%): 536 (M+Na⁺, 20), 514 (M+H⁺, 100).

EXAMPLE 98 Mixture of (R)-1-[6-[(S)- and(RS)-1-[6-[(RS)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0683] a) 1H-Pyrrole-2-carboxylic acid benzyl ester

[0684] Lit. J. Org. Chem., 44:975 (1979). To a stirred solution of 5.0 g(45.0 mmol) pyrrole-2-carboxylic acid and 31.3 ml (225 mmol)triethylamine in 100 ml DMF was added dropwise 26 ml (225 mmol) benzylbromide and stirring continued for 72 h at room temperature. Thereaction mixture was then concentrated in vacuo and the residueresuspended in dichloromethane and washed twice with saturated sodiumbicarbonate solution and twice with water, and the aqueous phasesback-extracted with dichloromethane. The combined organic extracts weredried over sodium sulphate and concentrated in vacuo. Flashchromatography (25% EtOAc in hexane) afforded 8.23 g (90%) of the titlecompound as a yellow oil. MS m/e (%): 201 (M⁺, 33), 94 ([M−OBn]⁺, 22),91 (Bn⁺, 100).

[0685] b)1-[6-(2-Benzyloxycarbonyl-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylicacid benzyl ester

[0686] To a stirred solution of 1.0 g (4.97 mmol)1H-pyrrole-2-carboxylic acid benzyl ester, 0.06 g (0.50 mmol)4-dimethylaminopyridine and 0.82 ml (5.47 mmol)1,8-diazabicyclo[5.4.0]undec-7-ene in 40 ml dichloromethane at 0° C. wasadded dropwise 0.36 ml (2.49 mmol) adipoyl chloride and stirringcontinued for 1 h at room temperature. The reaction mixture was thenwashed sequentially with 1 M hydrochloric acid, saturated sodiumbicarbonate solution and finally with saturated brine, and the aqueousphases back-extracted with dichloromethane. The combined organicextracts were dried over sodium sulphate and concentrated in vacuo.Flash chromatography (25% EtOAc in hexane) afforded 450 mg (35%) of thetitle compound as a white crystalline solid. MS m/e (%): 530 (M+NH₄ ⁺,100).

[0687] c) Mixture of (R)-1-[6-[(S)- and(RS)-1-[6-[(RS)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylicacid

[0688] Using General Procedure B with 800 mg (1.56 mmol)1-[6-(2-benzyloxycarbonyl-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylicacid benzyl ester afforded 470 mg (91%) of the title compound as a whitecrystalline solid. MS m/e (%): 339 ([M−H]⁻, 100).

EXAMPLE 991-[6-(2-Carboxy-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylicacid

[0689] a) 1H-Pyrrole-2-carboxylic acid tert-butyl ester

[0690] Lit. Tetrahedron, 41:5633 (1985). To a stirred solution of 10.0 g(90.0 mmol) pyrrole-2-carboxylic acid in 180 ml dioxane was addeddropwise at 0° C. 18 ml concentrated sulphuric acid 2-methylpropene wasthen condensed into the reaction flask over the course of 1 h, using adry-ice condenser, and stirring continued for 16 h at 0° C. while thedry-ice condenser was periodically refilled so as to maintain a slowreflux of 2-methylpropene. The reaction mixture was then pouredcautiously into an ice-cooled mixture of 400 ml ether and 150 ml 2 Msodium hydroxide solution. The phases were separated and the aqueousphase extracted twice more with ether. The combined organic phases werewashed successively with 2 M sodium hydroxide solution, water andfinally with saturated brine, then dried over sodium sulphate andconcentrated in vacuo to afford 9.07 g (60%) of the title compound as acolorless oil which still contained some dioxane. ¹H NMR d (250 MHz,CDCl₃) 9.60 (1H, br s), 6.90 (1H, m), 6.83 (1H, m), 6.22 (1H, m), 1.56(9H, s).

[0691] b)1-[6-(2-tert-Butoxycarbonyl-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylicacid tert-butyl ester

[0692] To a stirred solution of 1.3 g (7.77 mmol)1H-pyrrole-2-carboxylic acid tert-butyl ester, 95 mg (0.78 mmol)4-dimethylaminopyridine and 1.28 ml (8.56 mmol)1,8-diazabicyclo[5.4.0]undec-7-ene in 40 ml dichloromethane at 0° C. wasadded dropwise 0.57 ml (3.91 mmol) adipoyl chloride and stirringcontinued for 16 h at room temperature. A further 95 mg (0.78 mmol)4-dimethylaminopyridine and 1.28 ml (8.56 mmol)1,8-diazabicyclo[5.4.0]undec-7-were added and stirring continued for afurther 4 h at room temperature. The reaction mixture was then washedsequentially with 1 M hydrochloric acid, saturated sodium bicarbonatesolution and finally with saturated brine, and the aqueous phasesback-extracted with dichloromethane. The combined organic extracts weredried over sodium sulphate and concentrated in vacuo. Flashchromatography (gradient: 10-20% EtOAc in hexane) afforded 464 mg (13%)of the title compound as a light yellow crystalline solid. MS m/e (%):462 (M+NH₄ ⁺, 100).

[0693] c)1-[6-(2-Carboxy-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylicacid

[0694] To a stirred solution of 55 mg (0.12 mmol)1-[6-(2-tert-butoxycarbonyl-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylicacid tert-butyl ester in 8 ml dichloromethane at 0° C. was addeddropwise 0.15 ml (1.97 mmol) trifluoroacetic acid and stirring continuedfor 16 h at room temperature. Concentration in vacuo and azeotropingthree times with chloroform on a rotary evaporator afforded 39 mg (95%)of the title compound as an off-white crystalline solid. MS m/e (%): 350(M+NH₄ ⁺, 100).

EXAMPLE 100(R)-1-[6-[(R)-2-Carboxy-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylicacid

[0695] a) (2R)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester1-tert-butyl ester

[0696] A solution of 15.6 ml (0.22mol) dimethylsulfoxide in 50 mldichloromethane was given to 9.60 ml oxalylchloride in 150 mldichloromethane at minus 65° C. during a period of 10 minutes. After 5minutes at −65° C. 32.1 g (0.1mol)(2R,2R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester1-tert-butyl ester in 100 ml dichloromethane were added and afteradditional 15 minutes 24.4 ml (0.18 mol) triethylamine. The cooling bathwas removed, stirring was continued over night, and then the mixture waspoured into ice-water. Extraction with dichloromethane, followed bywashing with 0.05 N HCl, bicarbonate and water and chromatography oversilicagel with dichloromethane/ethylacetate 98:2 gave 11.1 g (35%)(2R)-4-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butylester as a colorless liquid.

[0697] MS m/e (%): 263(M-isobutylene, 7), 219 (8), 184 (24), 128 (14),91 (58), 84 (40), 57 (100); [α]_(D)=+1.1° (c=1% in methanol).

[0698] b) (2R)-4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzylester 1-tert-butyl ester

[0699] A solution of 0.64 g (0.002 mol)(2R)-4-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butylester in 3 ml dichloromethane was treated at 0° C. with 0.79 ml (0.006mol) diethylaminosulfur trifluoride, stirring was continued at roomtemperature for 32 hours and then the mixture was poured on ice.Extraction with dichloromethane and filtration over silicagel withhexane followed by elution with dichloromethane gave 0.62 g (90%)(2R)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester1-tert-butyl ester as light yellow oil.

[0700] MS m/e (%): 285(1), 206 (6), 106 (33), 91 (35), 57 (100);[α]_(D)=+43.0° (c=1% in methanol).

[0701] c) (2R)-4,4-Difluoro-pyrrolidine-2-carboxylic acid benzyl esterhydrochloride (1:1)

[0702] 100 ml of dry HCl in diethylether was added to a solution of 7.51g (0.022 mol) (2R)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid2-benzyl ester 1-tert-butyl ester in a mixture 100 ml diethylether and20 ml dichloromethane. After stirring for two days 5.84 g (96%)(2R)-4,4-difluoro-pyrrolidine-2-carboxylic acid benzyl esterhydrochloride (1:1) were isolated by filtration and dried under reducedpressure.

[0703] Mp.: 118-120° C.; [α]_(D)=+29.3° (c=1% in methanol).

[0704] d)(R)-1-[6-[(R)-2-Benzyloxycarbonyl-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester

[0705] To a suspension of 1.11 g (0.004 mol)(2R)-4,4-difluoro-pyrrolidine-2-carboxylic acid benzyl esterhydrochloride (1:1) in 20 ml dichloromethane were added 1.17 ml (0.008mol) triethylamine, and 0.29 ml (0.002 mol) adipoyldichloride in 5 mldichloromethane. After stirring at room temperature over night themixture was extracted with 1N HCl, water and aqueous sodiumbicarbonateand dried with sodiumsulfate. Chromatography over silicagel withdichloromethane/ethylacetate 8:2 gave 0.79 g (66%)(R)-1-[6-[(R)-2-benzyloxycarbonyl-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester as colorless oil.

[0706] ISP-MS: 593 (MH)⁺; [α]_(D)=+67.3° (c=1% in methanol).

[0707] e)(R)-1-[6-[(R)-2-Carboxy-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylicacid

[0708] 0.59 g (0.001 mol)(R)-1-[6-[(R)-2-Benzyloxycarbonyl-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester in 20 ml ethanol were hydrogenated at room temperatureand atmospheric pressure in the presence of 0.12 g 5% palladium/carbon.After completion of the reaction the catalyst was filtered off, thesolvent was distilled off, and the residue was dissolved indichloromethane. Evaporation gave 0.4 g (97%)(R)-1-[6-[(R)-2-carboxy-4,4-difluoro-pyrrolidin-1-yl]-6-oxo-hexanoyl]-4,4-difluoropyrrolidine-2-carboxylicacid as a white foam. ISP-MS: 413 (MH)^(+; [α]) _(D)=+54.2° (c=1% indimethylsulfoxide).

EXAMPLE 101(R)-1-[[2-[2-[(R)-2-Carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid

[0709] a)(R)-1-[[2-[2-[(R)-2-Benzyloxycarbonyl-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester

[0710] To a mixture of 1.11 g (0.004 mol)(2R)-4,4-difluoro-pyrrolidine-2-carboxylic acid benzyl esterhydrochloride (1:1), 0.45 g (0.002 mol) 1,2-phenylenedioxydiacetic acid,1.21 g (0.012 mol) N-methylmorpholine, and 0.61 g (0.004mol)1-hydroxybenzotriazole hydrate in 90 ml dichloromethane were added 0.77g (0.004 mol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidhydrochloride. After stirring at room temperature for 18 hours themixture was extracted with 1N HCl, water, 10% aqueous sodium bicarbonateand again water. Chromatography over silicagel withdichloromethane/ethylacetate 9:1 yielded 0.52 g (39%)(R)-1-[[2-[2-[(R)-2-benzyloxycarbonyl-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester as colorless oil. ISP-MS: 673 (MH)⁺; [α]_(D)=+68.4°(c=1% in methanol).

[0711] b)(R)-1-[[2-[2-[(R)-2-Carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid

[0712] 0.47 g (0.0007mol)(R)-1-[[2-[2-[(R)-2-Benzyloxycarbonyl-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester in 20 ml ethanol were hydrogenated at room temperatureand atmospheric pressure in the presence of 0.09 g 5% palladium/carbon.After completion of the reaction the catalyst was filtered off, thesolvent was distilled off, and the residue was dissolved indichloromethane. Evaporation gave 0.32 g (94%)(R)-1-[[2-[2-[(R)-2-carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid as a light yellow foam. ISP-MS: 493 (MH)⁺; [α]_(D)=+46.8° (c=1% indimethylsulfoxide).

EXAMPLE 102(R)-1-[[4-[2-[(R)-2-Carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid

[0713] a)(R)-1-[[4-[2-[(R)-2-Benzyloxycarbonyl-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester

[0714] To a mixture of 1.11 g (0.004 mol)(2R)-4,4-difluoro-pyrrolidine-2-carboxylic acid benzyl esterhydrochloride (1:1), 0.39 g (0.002 mol) 1,4-phenylenediacetic acid, 1.21g (0.012 mol) N-methylmorpholine, and 0.61 g (0.004mol)1-hydroxybenzotriazole hydrate in 90 ml dichloromethane were added 0.77g (0.004 mol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidhydrochloride. After stirring at room temperature for 18 hours themixture was extracted with 1N HCl, water, 10% aqueous sodium bicarbonateand again water. Chromatography over silicagel withdichloromethane/ethylacetate 9:1 yielded 0.72 g (56%)(R)-1-[[4-[2-[(R)-2-benzyloxycarbonyl-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester as colorless oil. ISP-MS: 658 (MNH₄)⁺; [α]_(D)=+55.5°(c=1% in methanol).

[0715] b)(R)-1-[[4-[2-[(R)-2-Carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid

[0716] 0.64 g (0.001 mol)(R)-1-[[4-[2-[(R)-2-Benzyloxycarbonyl-4,4-difluoropyrrolidin-1-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid benzyl ester in 20 ml ethanol were hydrogenated at room temperatureand atmospheric pressure in the presence of 0.13 g 5% palladium/carbon.After completion of the reaction the catalyst was filtered off, thesolvent was distilled off, and the residue was dissolved indichloromethane. Evaporation gave 0.28 g (61%)(R)-1-[[4-[2-[(R)-2-carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylicacid as a light yellow foam. ISP-MS: 478 (MNH₄)⁺; [α]_(D)=+50.3°(c=0.33% in dimethylsulfoxide).

EXAMPLE 103 (R)-1-[6-[(R)-2-Carboxy-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylic acid

[0717] a) (2R,4R)-4-(Toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylicacid 2-benzyl ester 1-tert-butyl ester

[0718] A solution of 2.35 g (0.007 mol)(2R,2R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl-ester1-tert-butyl ester in 22 ml pyridine were treated at 5° C. with 1.53 g(0.008 mol) p-toluenesulfonyl chloride and kept in the refrigerator for15 days. The pyridine was then distilled off in vacuo and the residuewas purified by chromatography on silicagel withdichloromethane/ethylacetate 95:5 to yield 2.81 g (81%)(2R,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid2-benzyl ester 1-tert-butyl ester as colorless liquid. MS m/e (%): 376(2), 340 (10), 284 (6), 240 (21), 91 (48), 68 (100), 57 (63);[α]_(D)=+24.5° (c=1% in methanol).

[0719] b) (2R,4S)-4-Phenylselanyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester

[0720] A solution of 7.99 g (0.026 mol) diphenyl diselenide in 250 mlethanol was treated with 1.59 g (0.042 mol) sodium borohydride andstirring was continued until the yellow solution turned colorless. Afteraddition of 20.0 g (0.042 mol)(2R,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid2-benzyl ester 1-tert-butyl ester the mixture was refluxed for 2.5hours. A white precipitate was filtered off and the solvent was removedin vacuo. Chromatography on silicagel with dichloromethane/methanol 98:2gave 8.48 g (51%) (2R,4S)-4-Phenylselanyl-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-ethyl ester as a colorless oil. MS m/e (%):399 (7),326 (13), 270 (18), 226 (38), 186 (35), 68 (60), 57 (100), 41(28). [α]_(D)=+40.4° (c=1% in methanol). Also isolated was 0.6 g(2R,4S)-4-phenylselanyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester1-tert-butyl ester as colorless oil. MS m/e (%): 461(7), 326 (21), 270(37), 248 (48), 226 (49), 209 (30), 91 (100), 68 (54), 57(96).[α]_(D)=+33.2° (c=1% in methanol).

[0721] c) (R)-2,5-Dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

[0722] To a solution of 7.35 g (0.016 mol)(2R,4S)-4-phenylselanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester in 80 ml dichloromethane were added at 0-5° C. 1.93ml (0.024 mol) pyridine and 4.6 ml 30% hydrogen peroxide and stirringwas continued for 1.5 hours. The mixture was extracted with 5% aqueousHCl, saturated aqueous sodium carbonate, and water. Chromatography onsilicagel with ethylacetate/hexane 1:5 yielded 2.99 g (77%)(R)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethylester as colorless oil. MS m/e (%): 186 (11), 168 (48), 140 (32), 112(100), 68 (85), 57 (58). [α]_(D)=+242° (c=1% in chloroform).

[0723] d) (R)-2,5-Dihydro-1H-pyrrole-2-carboxylic acid ethyl estertrifluoroacetate

[0724] (1:1) 1.5 g (0.006mol) (R)-2,5-dihydro-pyrrole-1,2-dicarboxylicacid 1-tert-butyl ester 2-ethyl ester were dissolved at 5° C. in 10 mltrifluoroacetic acid and stirring was continued at room temperature for3 hours. Evaporation of the solvent in vacuo gave 2.05 g (quant.) of(R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl estertrifluoroacetate (1:1) as a yellow oil. MS m/e (%): 142 (1), 68 (100),45 (10), 41 (15). [α]_(D)=+95.4° (c=1% in methanol).

[0725] e) (R)-1-[6-[(R)-2-Ethyloxycarbonyl-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylicacid ethyl ester

[0726] To a suspension of 0.99 g (0.003mol(R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl estertrifluoroacetate (1:1) in 20 ml dichloromethane were added 1.3 ml (0.009mol) triethylamine, and 0.22 ml (0.0015 mol) adipoyldichloride in 5 mldichloromethane. After stirring at room temperature over night themixture was extracted with 1N HCl, water and aqueous sodiumbicarbonateand dried with sodiumsulfate. Chromatogaphy over silicagel withethylacetate gave 0.37 g (32%)(R)-1-[6-[(R)-2-ethyloxycarbonyl-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylicacid ethyl ester as yellow oil. ISP-MS: 393 (MH)⁺.

[0727] f)(R)-1-[6-[(R)-2-Carboxy-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylicacid

[0728] 0.09 g (0.0002 mol)(R)-1-[6-[(R)-2-ethyloxycarbonyl-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylic acid ethyl ester were stirredwith aqueous HCl at 50° C. for 3 hours. The solvent was evaporated andthe residue dissolved in water and lyophilized to yield 0.08 g (97%)(R)-1-[6-[(R)-2-carboxy-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylicacid as light yellow foam. ISP-MS: 335 (M−H)⁻.

EXAMPLE 104(R)-1-[[2-[2-[(R)-2-Carboxy-2,5-dihydropyrrole-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-2,5-dihydropyrrole-2-carboxylicacid

[0729] a)(R)-1-[[2-[2-[(R)-2-Ethylcarbonyl-2,5-dihydropyrrole-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-2,5-dihydropyrrole-2-carboxylicacid ethyl ester

[0730] To a mixture of 0.99 g (0.003 mol)(R)-2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl estertrifluoroacetate (1:1), 0.34 g (0.0015 mol) 1,2-phenylenedioxydiaceticacid, 1.3 ml (0.012 mol) N-methylmorpholine, and 0.46 g (0.003 mol)1-hydroxybenzotriazole hydrate in 80 ml dichloromethane were added 0.57g (0.003 mol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidhydrochloride. After stirring at room temperature for 18 hours themixture was extracted with 1N HCl, water, 10% aqueous sodium bicarbonateand again water. Chromatography over silicagel with ethylacetate yielded0.45 g (32%)(R)-1-[[2-[2-[(R)-2-ethylcarbonyl-2,5-dihydropyrrole-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-2,5-dihydropyrrole-2-carboxylicacid ethyl ester as colorless oil. ISP-MS: 473 (MH)⁺.

[0731] b)(R)-1-[[2-[2-[(R)-2-Carboxy-2,5-dihydropyrrole-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-2,5-dihydropyrrole-2-carboxylicacid

[0732] 0.17g (0.0004 mol)(R)-1-[[2-[2-[(R)-2-ethylcarbonyl-2,5-dihydropyrrole-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-2,5-dihydropyrrole-2-carboxylicacid ethyl ester were stirred with aqueous HCl at 50° C. for 3 hours.The solvent was evaporated and the residue dissolved in water andlyophilized to yield 0.1 3 g (86%)(R)-1-[[2-[2-[(R)-2-carboxy-2,5-dihydropyrrole-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-2,5-dihydropyrrole-2-carboxylic acid as white amorphous powder. ISP-MS:417 (MH)⁺.

EXAMPLE A

[0733] Tablets of the following composition were manufactured in theusual manner: mg/tablet Active ingredient 100  Powd. lactose 95 Whitecorn starch 35 Polyvinylpyrrolidone  8 Na carboxymethylstarch 10Magnesium stearate  2 Tablet weight 250 

EXAMPLE B

[0734] Tablets of the following composition are manufactured in theusual manner: mg/tablet Active ingredient 200  Powd. lactose 100  Whitecorn starch 64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20Magnesium stearate  4 Tablet weight 400 

EXAMPLE C

[0735] Capsules of the following composition are manufactured:mg/capsule Active ingredient 50 Cryst. lactose 60 Microcrystallinecellulose 34 Talc  5 Magnesium stearate  1 Capsule fill weight 150 

[0736] The active ingredient having a suitable particle size, thecrystalline lactose and the microcrystalline cellulose are homogeneouslymixed with one another, sieved and thereafter talc and magnesiumstearate are admixed. The finished mixture is filled into hard gelatinecapsules of suitable size.

[0737] The subject invention has been described in terms of itspreferred embodiments. Upon reading the present specification certainalternative embodiments will become obvious to those skilled in the art.These variations are to be considered within the scope and spirit of thesubject invention which is only to be limited by the claims that followand their equivalents.

What is claimed is:
 1. A D-proline compound of the formula:

wherein R is SH; benzyl; benzyl substituted by hydroxy or lower alkoxy;phenyl; phenyl substituted by hydroxy or lower alkoxy; or the group

R¹ is hydrogen or halogen; X is —(CH₂)_(n)—; —CH(R²)(CH₂)_(n)—;—CH₂O(CH₂)_(n)—; —CH₂NH—; benzyl; —C(R²)═CH—; —CH₂CH(OH)—; orthiazol-2,5-diyl; R² is lower alkyl, lower alkoxy, or benzyl;

is a single or a double bond; and n is 0-3, or a pharmaceuticallyacceptable salt, monoester, or diester thereof, with the exception of(R)-1-[(R)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acidand (R)-1-[(S)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylicacid.
 2. The compound according to claim 1, wherein R is SH.
 3. Thecompound according to claim 2, wherein X is —CH(R²)(CH₂)_(n)—, R² ismethyl or methoxy, and n is 0 or
 1. 4. The compound according to claim 3which is1-[(S)3-mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acid.5. The compound according to claim 3 which is1-[(R)3-mercapto-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acid.6. The compound according to claim 1, wherein R is the group


7. The compound according to claim 6, wherein X is —(CH₂)_(n)—.
 8. Thecompound according to claim 7 which is(R)-1-[[(R)-2-carboxy-pyrrolidin-1-yl]-acetyl]-pyrrolidine-2-carboxylicacid.
 9. The compound according to claim 1, wherein X is —CH₂O(CH₂)_(n)—and n is 0 or
 1. 10. The compound according to claim 9 which is(R)-1-[(4-hydroxy-3-methoxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylicacid.
 11. The compound according to claim 9 which is(R)-1-[(4-hydroxy-2-methoxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylicacid.
 12. The compound according to claim 1, wherein R is benzyl. 13.The compound according to claim 12, wherein X is —CH₂NH—.
 14. Thecompound according to claim 13 which is(R)-1-benzylaminoacetyl-pyrrolidine-2-carboxylic acid.
 15. The compoundaccording to claim 1 which is(R)-1-[(3-hydroxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acid.